T-2毒素的代谢和毒作用信号转导研究
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摘要
T-2毒素由镰刀菌(Fusarium)产生,是单端孢霉烯族毒素类中毒性最强的毒素。粮食作物,尤其小麦、大麦、燕麦和玉米是T-2毒素主要的污染对象。通过污染饲料,T-2毒素对动物和动物性食品消费者健康造成危害。T-2毒素与核糖体结合或破坏线粒体功能来抑制细胞的蛋白质和核酸的合成,通过激活MAPK、JAK/STAT等信号转导通路,导致炎性细胞因子的表达,诱导细胞凋亡和坏死。
T-2毒素的代谢途径与毒性产生密切相关。T-2毒素进入动物体内被代谢成各种产物,其毒性差异变化巨大。HT-2毒素、3’-OH-T-2毒素和Neosolaniol(NEO)等是T-2毒素在动物体内的主要代谢产物。与T-2毒素相比,一些代谢产物毒性降低,但有些代谢物的毒性升高。研究清楚T-2毒素的代谢途径和主要代谢产物是揭示其在动物体内如何发挥毒性的重要前提。所以,揭示T-2毒素在动物中,尤其是食品动物中的代谢途径,对毒性机理研究的开展和食品安全以及人类健康等方面至关重要。然而,迄今为止,人们尚未清楚T-2毒素在食品动物中的整体代谢特点,尤其是不同种属动物对T-2毒素代谢转化存在着何种异同,尚无系统研究。
T-2毒素引起核糖体和线粒体的损伤并最终导致细胞凋亡与T-2毒素迅速激活MAPK信号通路密切相关。MAPK被证明是单端孢霉烯族毒素发挥细胞毒性的重要信号通路之一。MAPK的激活迅速而短暂,但与细胞凋亡密切相关的炎性细胞因子,如IL-6、TNF-α和IL-1β等的激活却是持续而缓慢的,所以MAPK通路下游很可能存在其它信号通路激活炎性因子。本实验室前期工作已经初步发现JAK/STAT是单端孢霉烯族毒素的下游信号通路之一,并与毒素的免疫毒性密切相关。然而,目前与T-2毒素毒性密切相关的MAPK和JAK/STAT信号通路的上下游关系仍是未知,两者的激活场所在哪里?哪些因子连接两者的传递?尚未有报道。
已有研究表明肝脏和肠道是代谢单端孢霉烯族毒素的主要场所。所以,本课题系统研究了T-2毒素在猪、鸡、鱼和大鼠肝微粒体、肝胞液以及肝细胞中的代谢情况。包括分析鉴定主要的代谢产物,讨论主要的代谢途径以及种属间代谢的异同。此外,为进一步完善T-2毒素在动物体内的代谢,本文以猪为例探讨了T-2毒素在猪盲肠道模型中的代谢和降解情况,从而与肝脏的代谢相呼应。在毒性机理研究上,本研究着重从T-2毒素作用后MAPK和JAK/STAT信号通路的相互交联转导关系,以及某些重要基因和蛋白的功能去揭示T-2毒素细胞毒性的潜在毒性机理。为此,本研究通过信号通路特异性抑制剂、免疫荧光/激光共聚焦和透射电镜等方法和手段研究了MAPK和JAK/STAT信号通路的交联转导关系,毒素的胞内毒性靶标,并深入探讨了JNK1和STAT3交联关系和功能。本研究对于寻找毒素的毒性化合物和残留标示物提供了重要的靶标信息,对阐释动物对毒素的耐受性机理、毒素的防控和人类以及动物疾病的预防有重要意义。毒作用信号转导研究也对深入认识T-2毒素的毒理机制以及信号在胞内外传递并行使功能研究有重要参考价值。
1.T-2毒素在动物肝脏中比较代谢研究
本研究首先制备了猪、鸡、大鼠、鲤和草鱼肝微粒体、肝胞液和肝细胞,加入NADPH生产系统,在37℃(鱼28℃)下与T-2毒素孵育2h后,样品经过沉淀蛋白、高速离心和过滤膜等前处理过程,采用HPLC-MS-IT-TOF检测鉴定代谢物,探讨T-2毒素在动物肝脏中的代谢途径,比较T-2毒素在不同动物种属间代谢的异同。
结果表明,T-2毒素在肝微粒体中主要被代谢成5种产物(MT1-5),分别为HT-2毒素(MT1、Neosolaniol (NEO)(MT2)、3'-OH-T-2毒素(MT3)、3'-OH-HT-2毒素(MT4)和T-2triol (MT5),同时还发现T-2毒素原形。在猪和鸡中发现HT-2毒素(MT1). NEO(MT2)、3'-OH-T-2毒素(MT3)和3'-OH-HT-2毒素(MT4)。大鼠肝微粒体中除发现上述4种代谢物外,还检测到T-2triol,证明大鼠肝脏代谢T-2毒素能力强于其他动物。与陆地动物显著不同,水生动物鲤肝微粒体中只检测到HT-2毒素、NEO、3'-OH-T-2毒素和微量3'-OH-HT-2毒素代谢物。草鱼中检测到3’-OH-T-2和3'-OH-HT-2毒素,但并未检测到HT-2毒素。3’-OH-T-2毒素和NEO是鱼类的主要代谢产物。陆地动物(猪、鸡和大鼠)生成HT-2毒素的相对含量比鱼类显著高p<0.05),但3’-OH-T-2的含量比鱼类显著低(p<0.05)。可见,水解反应生成HT-2毒素是陆地动物肝脏微粒体的主要代谢方式,羟基化反应是鱼类肝脏代谢T-2毒素的主要方式。
肝胞液中发现了HT-2毒素(MT1)、NEO (MT2)和3’-OH-T-2毒素(MT3),但并未发现3'-OH-HT-2毒素,且3’-OH-T-2毒素的相对含量也非常低。鲤中未发现羟基化代谢物,因此肝胞液中代谢酶的羟基化能力低于肝微粒体。
猪、鸡和大鼠肝细胞中,除T-2毒素外,均发现了水解代谢产物HT-2毒素和NEO,且HT-2毒素所占的比例高于NEO。猪代谢产生HT-2毒素能力最强,鸡最弱。肝细胞中未发现羟基化代谢物。
上述研究表明,T-2毒素在动物肝脏中的代谢存在相似性和差异性。水解(生成HT-2毒素、NEO和T-2triol)和羟基化(3’-OH-T-2和3'-OH-HT-2)是T-2毒素在动物肝脏中的主要代谢方式。猪、鸡和大鼠中常见代谢物HT-2毒素在草鱼和鲤肝脏中很少产生,鱼类中3’-OH-T-2占主导地位。水解生成HT-2毒素是陆地动物猪、鸡和大鼠的共同主要代谢途径,而鱼类中羟基化是主要的代谢方式,表明鱼类对T-2毒素的代谢与陆地动物存在较大差异。鱼类和陆地动物肝脏中CYP450单加氧酶和羧酸酯酶的种类,以及对羟基化和水解催化能力的差异可能是造成T-2毒素代谢途径不同的重要原因。本研究进一步完善了T-2毒素在肝脏中的代谢机制,对T-2毒素的残留监控和残留标示物的确定以及毒理机制研究具有重要的指导意义。
2.T-2毒素在猪盲肠模型中代谢和降解研究
将T-2毒素与来自1头猪的盲肠内容物(Cecum)在厌氧环境下培养20min、40min、1h、2h、4h、8h和24h,采用槲皮素(Quercetin)检测微生物的正常活性,试验重复4头猪(Cecum1-4)。样品通过QuEChERS方法进行前处理,采用Agilent1100HPLC串联API4000QTrap质谱定量T-2毒素的降解和代谢物。潜在代谢物的鉴定采用精确质谱Thermo HPLC串联LTQ Orbitrap XL-HESI检测。本研究与肝脏的数据结合,将更好的揭示T-2毒素的代谢途径和生物利用度。
与盲肠Cecum4降解T-2毒素能力相比,来自另外3头猪盲肠(Cecum1-3)微生物降解T-2毒素的能力显著低(p<0.05)。在盲肠Cecum1-3中,T-2毒素降解在31.1-45.9%之间。而在盲肠Cecum4中,T-2毒素降解迅速,8h后T-2毒素剩余26.6±0.6%,24h后仅有3.0±0.1%的T-2毒素被检测到。所以来自不同猪的盲肠对T-2毒素的降解存在很大个体差异性。
孵育24h后代谢物除HT-2毒素外,未检测到其它代谢物。在盲肠Cecum4中,孵育8h后HT-2毒素并未进一步降解代谢,但在24h时间点相对低的回收率可能预示着HT-2毒素被代谢成其它化合物,但生成的量低于HPLC-MS/MS仪器的最低检测限(LOD)。T-2毒素对猪的毒性很有可能是由T-2和HT-2毒素的混合毒性造成。盲肠孵育中代谢物只发现了HT-2毒素,其他脱环氧等代谢物均未发现。因此,当研究T-2毒素的毒性时,HT-2毒素的机体吸收也不容忽视。当T-2毒素到达大肠后,代谢成HT-2毒素也可被机体吸收并造成危害。T-2毒素在盲肠中的代谢和降解研究,进一步补充了肝脏中的代谢数据,丰富了T-2毒素的肝肠代谢信息,为T-2毒素的体内代谢和毒性研究提供重要参考。
3.T-2毒素介导的MAPK和JAK/STAT信号通路交联转导研究
为深入研究T-2毒素介导的MAPK和JAK/STAT信号通路之间的交联转导关系,将T-2毒素(14nM)与RAW264.7细胞共同孵育不同时间(0.5、1、2、4、8、12和24h),通过信号通路特异性抑制剂研究信号通路中p38/MAPK和JAK、 STAT之间的相互转导关系,此外还关注了连接两个信号通路之间可能的结点,并通过透射电镜观测了胞内细胞器在T-2毒素影响下超显微结构病变,寻找T-2毒素胞内潜在的毒性靶标,从而为分子毒理研究提供更直观的证据。通过特异性抑制剂、免疫荧光/激光共聚焦和流式细胞仪等方法和手段,本文初步探讨了JNK和STAT基因的功能。最后,关注了T-2毒素的毒性与胞内代谢和浓度的相关关系。
研究结果发现,ERK、JNK1和p38MAPK基因能够被T-2毒素在1-2h内迅速激活,随后又快速沉寂,说明MAPK为一个快速反应通道。JAK2和STAT3基因被T-2毒素激活后并上调,但与MAPK信号通路不同,JAK/STAT信号通路激活过程缓慢,在12h才出现显著的上调。因此,在RAW264.7细胞中JAK/STAT是MAPK通路的一个下游通路,可能传递着来自MAPK的信号。IL-6在众多炎性细胞因子中基因上调最为显著,2h后上调30.43倍,12h后上调48.47倍。因此,IL-6在MAPK和JAK/STAT的信号传递中,可能发挥中至关重要的作用。
为更好的研究信号通路之间的上下游关系,通过相应的特异性抑制剂干预,观测其他基因及其蛋白磷酸化的表达。加入JNK1特异性抑制剂SP600125后,T-2毒素诱导的JAK2、ERK1/2和K-Ras的基因表达均受到显著抑制(p<0.05)。STAT3mRNA表达活性也受到显著抑制(p<0.05),但STAT1mRNA并未出现显著抑制效应。T-2毒素诱导IL-6基因表达在12h出现了显著的抑制p<0.05)。T-2毒素激活JNK1后,信号通过JAK2传导,随后通过STAT3传递,其中IL-6和K-Ras在MAPK和JAK/STAT信号通路中发挥着纽带传递作用。阻断JNK1活性后,CIS、SOCS1和SOCS2基因显著上调表达(p<0.05),说明JNK1对此SOCS的3个亚家族进行负调控,但阻断JNK1后SOCS3基因下调,表明JNK1对SOCS3为正调控关系。
RAW264.7细胞中T-2毒素诱导后,JNK1信号经JAK2、STAT3、ERK和p38传导,激活的JAK2、STAT3、ERK和p38基因又可调控JNK1基因表达。阻断STAT3表达后,T-2毒素诱导的IL-6基因在12h受到显著抑制(p<0.05)。综合研究结果,IL-6激活JAK2/STAT3通路后,STAT3又可继续激活IL-6后续基因表达,进入下一循环,继续发挥作用。
经T-2毒素诱导后JNK1蛋白迅速磷酸化,并在1h开始转入细胞核内,随后会从核内返回胞质,但仍会继续进入核内。T-2毒素引起的p-JNK1穿梭入核至少持续12h。阻断JNK1活性后,STAT3磷酸化和入核均受到抑制,但STAT1未受影响。表明RAW264.7细胞中,T-2毒素诱导的STAT3磷酸化和入核发挥功能均受JNK1调控。
透射电镜观测结果显示,RAW264.7细胞与T-2毒素(14nM)孵育12h后,内质网扩张、线粒体肿大、核质边缘化,表明细胞出现了凋亡症状。28nMT-2毒素作用细胞12h后,核质完全边缘化,内质网扩张甚至形成空泡,线粒体肿胀,粗面内质网上核糖体出现脱粒,出现严重凋亡症状。观测结果表明T-2毒素主要作用于核糖体和线粒体。
阻断JNK1表达后,线粒体出现了明显肿胀,细胞凋亡率显著上升,基因Bcl-2/Bax和Bcl-xL/Bax比值均出现显著下降p<0.05),Caspase-3和Caspase-9基因水平显著上调,凋亡数据进一步验证了细胞超显微结构病变,表明JNK1具有保护RAW264.7细胞线粒体功能。阻断STAT3活性后,Bcl-2/Bax和Bcl-xL/Bax比值也出现明显下调p<0.05),进一步证明JNK1-STAT3为一条细胞保护通路,此通路可能通过保护线粒体的正常功能来抑制T-2毒素诱导的细胞凋亡。另一方面,本研究也证明T-2毒素是一把双刃剑,具有两面性,这一点也进一步丰富了对T-2毒素细胞毒性机理的认识。
液相质谱检测结果显示,在12h时细胞内T-2毒素含量显著高于2h时的含量。电镜超显微结构也观测到12h时细胞受损比2h时更加严重,表明T-2毒素长时间接触RAW264.7细胞,对其产生更高的毒性。2h后检测到的代谢物有HT-2毒素和3’-OH-T-2毒素,12h为3’-OH-T-2毒素,但含量甚低,T-2毒素始终是细胞内主要的毒性物质。
RAW264.7细胞中T-2毒素刺激后,MAPK和JAK/STAT信号通路之间存在错综复杂的交联转导关系。本研究揭示了IL-6和K-Ras在连接MAPK和JAK/STAT信号转导中发挥重要功能。[NK1-STAT3信号通路受T-2毒素刺激后发挥了保护线粒体,抑制细胞凋亡的功能。T-2毒素激活凋亡通路的同时,也能激活细胞的保护通路,抑制细胞的凋亡。T-2毒素靶向性损害RAW264.7细胞的线粒体和核糖体。T-2毒素进入细胞后,虽被代谢成多种物质,但T-2毒素仍占主导地位调控信号转导。
综上所述,本文首先研究了T-2毒素在肝脏和盲肠中的代谢,阐明了T-2毒素在不同种属动物中的代谢途径和特点,鉴定出5种主要代谢产物,充分完善了T-2毒素的代谢机制,对T-2毒素的残留监控及残留标示物的确定具有重要的指导意义。T-2毒素诱导下MAPK和JAK/STAT信号通路交联转导关系研究,进一步揭示了T-2毒素的毒性机制,为毒素防控、疾病预防、癌症治疗和新药开发提供了重要参考。
As one of the primary members of type-A trichothecenes, T-2toxin is produced mainly by Fusarium genus. T-2toxin is the greatest toxic one for animals among trichothecenes, and it could contamiant cereals such as wheat, barley, oats, and maize. T-2toxin is making a great harmful on animals and humans through feed contaimination. Importantly, T-2toxin could also inhibit the sysnthesis of protein, DNA and RNA through conjugating with ribosomes as well as the damage of mitochondria. This toxin could also activate MAPK and JAK/STAT signaling pathways as well as cytokine expression and induce cell apoptosis and immune dysfunction.
Metabolism of T-2toxoin has a close relationship with its toxicities. HT-2toxin,3'-OH-T-2, and neosolaniol (NEO) are the major metabolites of T-2toixn in animals. The toxicities change greatly once T-2toxin is biotransformed into different productes. The toxicity of most metabolites such as NEO and T-2triol are decreased. However, the toxicities of some metabolites such as3'-OH-T-2, are not decreased significantly, or even display a slightly higher toxicity. Thus, elucidation of the metabolic pathways and identifying the major metabolites of T-2toxin in animals are prerequisite to reveal its toxicity in animals, and are also crucial for food safety and human health. However, up to date, a global metabolism of T-2toxin in food producing animals is still unclear; especially the metabolic profiles are never compared in different species.
T-2toxin can cause damage on ribosomes and mitochondria and ultimately lead to cell apoptosis. MAPK signaling pathway is proved to be an important toxicological pathway of trichothecenes and plays critical roles in toxicity. T-2toxin can active this pathway rapidly and transiently. It is known that animals are normally exposed to trichothecenes slowly. The effects of inflammatory cytokines on cells are performed slowly and continually. For example, IL-6, IL-1β, and TNF-a were found to be activated after12h by trichothecenes in RAW264.7cells. MAPK is proved to be an important target signaling pathway of trichothecenes and could be activated in a rapid and transient way. Thus, a contradiction rises when trying to explain the rapid MAPK activation but slow activation of inflammatory factors. We suspect that some other signal pathways might exist at the downstream to transmit the signals from MAPKs and activate the inflammatory factors. Indeed, it is already proved from our previous work that JAK/STAT pathway are the downstream targets of trichothecenes and played important roles in regulation of proinflammatory cytokines as well as apoptosis. However, the upstream and downstream interrelationship between MAPK and JAK/STAT signal pathways is still unclear. Where do they peform their fuctions once they are activated, in nucleus or cytoplasm? What are the messengers to connect the two pathways and transmite the signals? All these questions need to be answered.
It is already known that T-2toxin can be well biotransformed in liver and intestine. Thus, we aimed to study the metabolism of T-2toxin in hepatic subcellular fractions (microsomes and cytosol) of pigs, chickens, rats, and carp (common carp and grass carp), as well as hepatocytes of rats, piglets and chickens. Based on the results, we discussed the metabolic difference of T-2toxin in different species. In addition, we also studied the degradation and metabolism of T-2toxin in pig cecum model. This study combined with the data in liver will further elucidate the metabolic fates of T-2toxin in animals. We also aim to study the cross talk between MAPK and JAK/STAT signaling pathways, which is induced by trichothecene T-2toxin. The cross talk between JNK1and STAT3were especially discussed. Specific inhibitors are useful tools to elucidate the signaling cross talk. In addition to the cross talk, we also monitored the typical ultrastructural changes of RAW264.7cells caused by T-2toxin and found out the potential toxicological targets of T-2toxin. The observation provides crucial visualized evidence for the molecular targets of trichothecenes. Finally, relationship between the toxic profiles and T-2toxin contents in intracellular in RAW264.7cells were also addressed. The results from this study will provide important data for explaning the sensitivity difference to T-2toxin in different animals, and is also important for identifying the residue markers as well as the prevention of disease. The study of signaling pathways will provide further information for the understanding of toxic mechanism of trichothecenes as well as the interrelationship between MAPK and JAK/STAT signaling pathways.
1. A comparation of hepatic metabolism of T-2toxin in pigs, chickens, carp and rats
Metabolic profiles of T-2toxin in the hepatocytes of food producing animals, pigs and chickens; rats-the major experimental model were compared. Metabolic pathways of T-2toxin in liver microsomes and cytosol of pigs, chickens, common carp, grass carp, and rats were also especially concerned. The metabolites were identified by HPLC-MS-IT-TOF.
In liver microsomes, five metabolites (MT1-5) were detected and identified. T-2toxin was mainly metabolized to HT-2toxin (MT1), neosolaniol (NEO)(MT2),3'-OH-T-2(MT3),3'-OH-HT-2(MT4), and T-2triol (MT5). T-2triol was only detectable in rat liver microsomes, implying that rat liver microsomes have stronger metabolic capability of T-2toxin than other species. In carp liver microsomes, HT-2toxin, NEO, and3'-OH-T-2were detected. Different with land animals, there was only trance amount of3'-OH-HT-2in carp liver microsomes. In grass carp,3'-OH-HT-2and3'-OH-HT-2, but not HT-2toxin were detected. The relative amount of HT-2toxin in land animals (pig, chicken, and rat) was much higher than that in carp (p<0.05). Hydrolysis to form HT-2toxin was the major metabolic pathway of T-2toxin in land animals (pig, chicken and rat). Different with land animals, HT-2toxin was not found in the liver microsomes of grass carp. In grass carp,3'-OH-T-2showed a relatively high amount, and followed with common carp. But in land animals, the capacity of transforming T-2toxin to3'-OH-T-2was relatively weak.
3'-OH-HT-2was not found in liver cytosol and the amount of3'-OH-T-2was also very low. Especially in common carp, the hydroxyl products were not found. Thus, we conclude that the hydroxyl capacity in liver cytosol is weaker than that in liver microsomes.
In hepatocytes, HT-2toxin and NEO were detectable. The amount of T-2toxin was much higher than NEO. Pigs produced a higher amount of HT-2toxin, chickens were the weakest. The hydroxyl products and C-8-deisovaleryl metabolites were not detected.
Taken together, there was a similarity in the metabolic pathways of T-2toxin among different species, but an interesting and different profile was also monitored. T-2toxin can be metabolized rapidly in liver. Hydrolysis (HT-2, NEO, and T-2triol) and hydroxylation (3'-OH-T-2and3'-OH-HT-2) were the major metabolic pathways in the liver from these species. Hydrolysis and forming HT-2toxin was the same pathway in these land animals. As compared with hydrolysis reaction, the hydroxylation was much weaker in land animals. But carp showed an opposite metabolic characteristic. HT-2, the very common metabolite in land animals, was rarely found in carp, but3'-OH-T-2was the major one. This result implies that the metabolism of T-2toxin in fish has some differences with land animals. The different characteristic of CYP450monooxygenase and carboxylesterase as well as the differece cataltic abilty in hydroxyaiton and hydrolysis actions by these enzymes between carp and land animals are possibly the reasons for the different metabolic profiles of T-2toxin. The findings of this study further improves the metabolic mechanism of T-2toxin and is also important for residue determination, residue marker identification as well as the toxic mechanism of trichothecenes.
2. Degradation and metabolism of T-2toxin in pig cecum model
To further provide the information of metabolism of T-2toxin in animals, a pig cecum model was produced to investigate the fate and degradation of T-2in animal intestines. The data combineding with liver metabolism will better uncover the metabolic pathways and bioavailbility of T-2toxin in animals.
T-2toxin was incubated with pig cecum at anaerobic conditions for20min,40min,1h,2h,4h,8h, and24h. Quercetin was used to monitor the activity of the bacterial in the pig cecum. The extraction of incubated samples was performed by a modified QuEChERS method. An Agilent1100series HPLC was linked to an API4000QTrap mass spectrometer. Heated Electrospray Ionization (HESI) coupled with a Thermo HPLC system was used to detect the potential metabolites.
Four different cecums were analyzed in comparison to the sterilized control. The degradation by the microbiota in Cecum1-3was much slower compared to Cecum4. In Cecum1-3, the degradation ranged31.1-45.9%of the originally incubated amount of T-2toxin. Only a small increase of the degradation between8and24h incubation time was detectable, e.g., only0.8%of T-2toxin was further degraded between8and24h in Cecum1. However, a very strong degradation was observed in Cecum4. About26±0.6%of T-2toxin were left after incubation for8h. Only3.0±0.1%of T-2toxin was detectable after24h.
Besides HT-2toxin, other metabolites, such as deepoxy-HT-2, were not detected. In Cecum4, the formed HT-2toxin was not further metabolized after a further incubation for8h. However, the relatively low recovery after24h incubation might indicate that HT-2toxin was possibly further metabolized to other products to an extent which was lower than the LOD of the HPLC-MS/MS equipment. Thus, we suspect that the toxic effects of T-2toxin in pigs are possibly afforded by the combination of T-2toxin and HT-2toxin.
In conclusion, T-2toxin is metabolized to HT-2toxin as the main metabolite by the intestinal microbiota of pigs with large interindividual difference. In one out of four analyzed cecums, T-2was nearly totally metabolized to HT-2toxin, whereas the other three cecums showed a degradation of T-2toxin up to46%. Besides HT-2toxin, no other metabolites were detectable in the incubated samples. For toxicity evaluations of T-2toxin in pigs, the combination of T-2and its major metabolite HT-2has to be considered, as both compounds show a similar cytotoxicity and absorption. The dagradation and metabolism study of T-2toxin in pig cecum further complemented the data of liver metaboism of T-2toxin and enriched the enterohepatic metabolic information; it also provides important references for the in vivo metabolism and toxic mechanism of T-2toxin.
3. The cross talk between MAPK and JAK/STAT signaling pathways induced by T-2toxin in RAW264.7cells
In order to study the cross talk between MAPK and JAK/STAT signaling pathway which is induced by T-2toxin, T-2toxin was incubated with RAW264.7cells for indicated time and the interrelationship between JNK, ERK, p38MAPK and JAK, STAT were investigated using the specific inhibitors. Furthermore, we studied the potential messengers between the two pathways. Besides the cross talk, we also monitored the typical ultrastructural changes of RAW264.7cells, which was caused by T-2toxin, and found out the potential toxicological targets of T-2toxin. This observation provides crucial visualized evidence for the molecular targets of trichothecenes. Moreover, the function of JNK1and STAT3were discussed using the inhibitors, immunoflourenscence and flow cytomery. Finally, the link between the toxic profiles and intracellular T-2toxin contents were addressed.
Results showed that the genes of ERK, JNK1and p38MAPK were activated within1-2h. However, they ceased quickly, implying that MAPK is a rapid signaling pathway. JAK2and STAT3mRNA were up regulated significantly, but they were slow and the highest peak was observed at12h. It is very possible that JAK/STAT pathway is the downstream singling of MAPK. IL-6among the studied cytokines showed the relatively highest up-regulation level, which was up regulated30.43-fold at2h and48.47-fold at12h. Thus, we suspected that IL-6possibly plays a very important role in the cross talk between MAPK and JAK/STAT signaling pathways. In addition, K-Ras had an important function in the cross talking, the up regulation after1and12h implying that K-Ras also plays roles in connecting the cross talk between MAPK and JAK/STAT.
In order to study the up-and down stream relationships, we used the specific inhibitors and monitored the gene levels and protein phosphorylation. When JNK1gene expression was blocked by its inhibitor SP600125, both the mRNA expression and protein phosphorylation of JAK2, and K-Ras response to T-2toxin were significantly suppressed. The gene expression and protein phosphorylation of STAT3, but not STAT1were significantly decreased. Interestingly, the gene expression of IL-6induced by T-2toxin was suppressed by SP600125at12h but not at2h. These results implies that the activated signals induced by T-2toxin could transfer from JNK1to JAK2/STAT3. Talk from JNK1to STAT3was possibly connected by IL-6. SOCS family is an important negatively regulator of JAK/STAT signaling pathway, we studied the relationships between JNK1and SOCS1,2,3, and CIS through blocking JNK1activity and found out that the mRNA expressions of CIS, SOCS1, and SOCS2were increased significantly, whereas the mRNA expression of SOCS3was decreased markedly. This observation implies that JNK1could regulate CIS, SOCS1, and SOCS2negatively, but positively regulate SOCS3.
Once induced by T-2toxin, signal of JNK1could transmit to JAK2, STAT3, ERK, and p38. Moreover, these activated genes can reversely regulate JNK1activity. Blocking STAT3activity, IL-6gene expression at12was suppressed remarkedly. Thus, we suspected that STAT3would further activate IL-6after the activation of JAK2/STAT3by IL-6and join in the next circulations.
JNK1was phosphorylated rapidly and imported into the nucleus, but the nucleus translocation is in a dynamic way and will later export to cytoplasm. When JNK1activity was blocked, the phosphorylation and nucleus translocation of STAT3were inhibited, but STAT1was not affected. This observation implies that phosphorylation and nucleus translocation of STAT3is JNK1-dependent.
When examined by transmission electron microscopy, mitochondrial swelling and the rough endoplasmic reticulum dilation were clearly visible when treated with T-2toxin at the level of14nM for12h. Once the toxin was increased to28nM, more serious morphological changes were observed. Besides the swelling mitochondria and the dilation of rough endoplasmic reticulum, polysomes on rough endoplasmic reticulum were also breakdown and degranulated. In addition, condensation and marginalization of chromatin aggregation were also monitored, which suggests that cells are induced to apoptosis by T-2toxin.
Interestingly, when the gene expression of JNK1was blocked, the apoptotic ratio was increased significantly than the blank or toxin treated group (p<0.05). This result demonstrates that JNK1induced by T-2toxin has an anti-apoptotic function in RAW264.7cells. The ratios of Bcl-xL/Bax and Bcl-2/Bax were both decreased after blocking JNK1or STAT3activity. The mRNA expression of Caspase-3and Caspas-9were markedly increased (p<0.05) when blocking JNK1and STAT3activities. These results further prove that the apoptosis induced by T-2toxin is a mitochondria-dependent caspase pathway. JNK1-STAT3pathway could inhibit apoptosis and its function is very possibly mediated by regulating the function of mitochondria. JNK1-STAT3is newly proved to be a cell survival pathway, and T-2toxin is shown to have a Janus face. This study adds to our further understanding of the toxic mechanism of trichothecenes.
Finally, the intracellular content of T-2toxin in different time points was detected. The content of T-2toxin was increased significantly at12h than at2h, indicating that intracellular content of T-2toxin can be accumulated with time increase. Moreover, T-2toxin can be biotransformed to HT-2toxin and3'-OH-T-2toxin at2h, whereas3'-OH-T-2toxin was the sole metabolite at12h in RAW264.7cells. But at the two time points, T-2toxin was the major product to perform the toxic effects and induced gene expression.
Taken together, a complicated cross talk between MAPK and JAK/STAT signaling pathways mediated by T-2toxin is reported for the first time. K-Ras and IL-6are proved to be critical messengers for the cross talk between JNK1and STAT3. Importantly, T-2toxin has a Janus face, which not only induces cell apoptosis, cell survival/defense pathways, such as JNK1-STAT3, could also be activated simultaneously. However, the cell defense signaling is possibly not strong and was swamped in the cell death signals, which makes it easily to be ignored. On the other hand, this study also reveals that cells could up regulate some defense signaling pathways when they are exposed to dangerous environment. This work also showes that ribosome and mitochondria are two major toxic targets of T-2toxin. The findings add to our further understanding of the toxic mechanisms of trichothecenes and the cross talk between MAPK and JAK/STAT signaling.
In summary, we first investigated the metabolism of T-2toxin in liver and intestine, and dentified5metabolites as well as the major metabolic pathways, also the metabolic profiles in different speices were compared. This study consummated the metabolic mechanism of T-2toxin, and provided crucial information for residue mornitoring and determination of residue marker of T-2toxin. The cross talk between MAPK and JAK/STAT signaling pathway further uncovered the toxic mechanism of T-2toxin and provide an important referece for toxin controlling, disease prevention, cancer treatment and drug development.
T-2毒素的代谢途径与毒性产生密切相关。T-2毒素进入动物体内被代谢成各种产物,其毒性差异变化巨大。HT-2毒素、3’-OH-T-2毒素和Neosolaniol(NEO)等是T-2毒素在动物体内的主要代谢产物。与T-2毒素相比,一些代谢产物毒性降低,但有些代谢物的毒性升高。研究清楚T-2毒素的代谢途径和主要代谢产物是揭示其在动物体内如何发挥毒性的重要前提。所以,揭示T-2毒素在动物中,尤其是食品动物中的代谢途径,对毒性机理研究的开展和食品安全以及人类健康等方面至关重要。然而,迄今为止,人们尚未清楚T-2毒素在食品动物中的整体代谢特点,尤其是不同种属动物对T-2毒素代谢转化存在着何种异同,尚无系统研究。
T-2毒素引起核糖体和线粒体的损伤并最终导致细胞凋亡与T-2毒素迅速激活MAPK信号通路密切相关。MAPK被证明是单端孢霉烯族毒素发挥细胞毒性的重要信号通路之一。MAPK的激活迅速而短暂,但与细胞凋亡密切相关的炎性细胞因子,如IL-6、TNF-α和IL-1β等的激活却是持续而缓慢的,所以MAPK通路下游很可能存在其它信号通路激活炎性因子。本实验室前期工作已经初步发现JAK/STAT是单端孢霉烯族毒素的下游信号通路之一,并与毒素的免疫毒性密切相关。然而,目前与T-2毒素毒性密切相关的MAPK和JAK/STAT信号通路的上下游关系仍是未知,两者的激活场所在哪里?哪些因子连接两者的传递?尚未有报道。
已有研究表明肝脏和肠道是代谢单端孢霉烯族毒素的主要场所。所以,本课题系统研究了T-2毒素在猪、鸡、鱼和大鼠肝微粒体、肝胞液以及肝细胞中的代谢情况。包括分析鉴定主要的代谢产物,讨论主要的代谢途径以及种属间代谢的异同。此外,为进一步完善T-2毒素在动物体内的代谢,本文以猪为例探讨了T-2毒素在猪盲肠道模型中的代谢和降解情况,从而与肝脏的代谢相呼应。在毒性机理研究上,本研究着重从T-2毒素作用后MAPK和JAK/STAT信号通路的相互交联转导关系,以及某些重要基因和蛋白的功能去揭示T-2毒素细胞毒性的潜在毒性机理。为此,本研究通过信号通路特异性抑制剂、免疫荧光/激光共聚焦和透射电镜等方法和手段研究了MAPK和JAK/STAT信号通路的交联转导关系,毒素的胞内毒性靶标,并深入探讨了JNK1和STAT3交联关系和功能。本研究对于寻找毒素的毒性化合物和残留标示物提供了重要的靶标信息,对阐释动物对毒素的耐受性机理、毒素的防控和人类以及动物疾病的预防有重要意义。毒作用信号转导研究也对深入认识T-2毒素的毒理机制以及信号在胞内外传递并行使功能研究有重要参考价值。
1.T-2毒素在动物肝脏中比较代谢研究
本研究首先制备了猪、鸡、大鼠、鲤和草鱼肝微粒体、肝胞液和肝细胞,加入NADPH生产系统,在37℃(鱼28℃)下与T-2毒素孵育2h后,样品经过沉淀蛋白、高速离心和过滤膜等前处理过程,采用HPLC-MS-IT-TOF检测鉴定代谢物,探讨T-2毒素在动物肝脏中的代谢途径,比较T-2毒素在不同动物种属间代谢的异同。
结果表明,T-2毒素在肝微粒体中主要被代谢成5种产物(MT1-5),分别为HT-2毒素(MT1、Neosolaniol (NEO)(MT2)、3'-OH-T-2毒素(MT3)、3'-OH-HT-2毒素(MT4)和T-2triol (MT5),同时还发现T-2毒素原形。在猪和鸡中发现HT-2毒素(MT1). NEO(MT2)、3'-OH-T-2毒素(MT3)和3'-OH-HT-2毒素(MT4)。大鼠肝微粒体中除发现上述4种代谢物外,还检测到T-2triol,证明大鼠肝脏代谢T-2毒素能力强于其他动物。与陆地动物显著不同,水生动物鲤肝微粒体中只检测到HT-2毒素、NEO、3'-OH-T-2毒素和微量3'-OH-HT-2毒素代谢物。草鱼中检测到3’-OH-T-2和3'-OH-HT-2毒素,但并未检测到HT-2毒素。3’-OH-T-2毒素和NEO是鱼类的主要代谢产物。陆地动物(猪、鸡和大鼠)生成HT-2毒素的相对含量比鱼类显著高p<0.05),但3’-OH-T-2的含量比鱼类显著低(p<0.05)。可见,水解反应生成HT-2毒素是陆地动物肝脏微粒体的主要代谢方式,羟基化反应是鱼类肝脏代谢T-2毒素的主要方式。
肝胞液中发现了HT-2毒素(MT1)、NEO (MT2)和3’-OH-T-2毒素(MT3),但并未发现3'-OH-HT-2毒素,且3’-OH-T-2毒素的相对含量也非常低。鲤中未发现羟基化代谢物,因此肝胞液中代谢酶的羟基化能力低于肝微粒体。
猪、鸡和大鼠肝细胞中,除T-2毒素外,均发现了水解代谢产物HT-2毒素和NEO,且HT-2毒素所占的比例高于NEO。猪代谢产生HT-2毒素能力最强,鸡最弱。肝细胞中未发现羟基化代谢物。
上述研究表明,T-2毒素在动物肝脏中的代谢存在相似性和差异性。水解(生成HT-2毒素、NEO和T-2triol)和羟基化(3’-OH-T-2和3'-OH-HT-2)是T-2毒素在动物肝脏中的主要代谢方式。猪、鸡和大鼠中常见代谢物HT-2毒素在草鱼和鲤肝脏中很少产生,鱼类中3’-OH-T-2占主导地位。水解生成HT-2毒素是陆地动物猪、鸡和大鼠的共同主要代谢途径,而鱼类中羟基化是主要的代谢方式,表明鱼类对T-2毒素的代谢与陆地动物存在较大差异。鱼类和陆地动物肝脏中CYP450单加氧酶和羧酸酯酶的种类,以及对羟基化和水解催化能力的差异可能是造成T-2毒素代谢途径不同的重要原因。本研究进一步完善了T-2毒素在肝脏中的代谢机制,对T-2毒素的残留监控和残留标示物的确定以及毒理机制研究具有重要的指导意义。
2.T-2毒素在猪盲肠模型中代谢和降解研究
将T-2毒素与来自1头猪的盲肠内容物(Cecum)在厌氧环境下培养20min、40min、1h、2h、4h、8h和24h,采用槲皮素(Quercetin)检测微生物的正常活性,试验重复4头猪(Cecum1-4)。样品通过QuEChERS方法进行前处理,采用Agilent1100HPLC串联API4000QTrap质谱定量T-2毒素的降解和代谢物。潜在代谢物的鉴定采用精确质谱Thermo HPLC串联LTQ Orbitrap XL-HESI检测。本研究与肝脏的数据结合,将更好的揭示T-2毒素的代谢途径和生物利用度。
与盲肠Cecum4降解T-2毒素能力相比,来自另外3头猪盲肠(Cecum1-3)微生物降解T-2毒素的能力显著低(p<0.05)。在盲肠Cecum1-3中,T-2毒素降解在31.1-45.9%之间。而在盲肠Cecum4中,T-2毒素降解迅速,8h后T-2毒素剩余26.6±0.6%,24h后仅有3.0±0.1%的T-2毒素被检测到。所以来自不同猪的盲肠对T-2毒素的降解存在很大个体差异性。
孵育24h后代谢物除HT-2毒素外,未检测到其它代谢物。在盲肠Cecum4中,孵育8h后HT-2毒素并未进一步降解代谢,但在24h时间点相对低的回收率可能预示着HT-2毒素被代谢成其它化合物,但生成的量低于HPLC-MS/MS仪器的最低检测限(LOD)。T-2毒素对猪的毒性很有可能是由T-2和HT-2毒素的混合毒性造成。盲肠孵育中代谢物只发现了HT-2毒素,其他脱环氧等代谢物均未发现。因此,当研究T-2毒素的毒性时,HT-2毒素的机体吸收也不容忽视。当T-2毒素到达大肠后,代谢成HT-2毒素也可被机体吸收并造成危害。T-2毒素在盲肠中的代谢和降解研究,进一步补充了肝脏中的代谢数据,丰富了T-2毒素的肝肠代谢信息,为T-2毒素的体内代谢和毒性研究提供重要参考。
3.T-2毒素介导的MAPK和JAK/STAT信号通路交联转导研究
为深入研究T-2毒素介导的MAPK和JAK/STAT信号通路之间的交联转导关系,将T-2毒素(14nM)与RAW264.7细胞共同孵育不同时间(0.5、1、2、4、8、12和24h),通过信号通路特异性抑制剂研究信号通路中p38/MAPK和JAK、 STAT之间的相互转导关系,此外还关注了连接两个信号通路之间可能的结点,并通过透射电镜观测了胞内细胞器在T-2毒素影响下超显微结构病变,寻找T-2毒素胞内潜在的毒性靶标,从而为分子毒理研究提供更直观的证据。通过特异性抑制剂、免疫荧光/激光共聚焦和流式细胞仪等方法和手段,本文初步探讨了JNK和STAT基因的功能。最后,关注了T-2毒素的毒性与胞内代谢和浓度的相关关系。
研究结果发现,ERK、JNK1和p38MAPK基因能够被T-2毒素在1-2h内迅速激活,随后又快速沉寂,说明MAPK为一个快速反应通道。JAK2和STAT3基因被T-2毒素激活后并上调,但与MAPK信号通路不同,JAK/STAT信号通路激活过程缓慢,在12h才出现显著的上调。因此,在RAW264.7细胞中JAK/STAT是MAPK通路的一个下游通路,可能传递着来自MAPK的信号。IL-6在众多炎性细胞因子中基因上调最为显著,2h后上调30.43倍,12h后上调48.47倍。因此,IL-6在MAPK和JAK/STAT的信号传递中,可能发挥中至关重要的作用。
为更好的研究信号通路之间的上下游关系,通过相应的特异性抑制剂干预,观测其他基因及其蛋白磷酸化的表达。加入JNK1特异性抑制剂SP600125后,T-2毒素诱导的JAK2、ERK1/2和K-Ras的基因表达均受到显著抑制(p<0.05)。STAT3mRNA表达活性也受到显著抑制(p<0.05),但STAT1mRNA并未出现显著抑制效应。T-2毒素诱导IL-6基因表达在12h出现了显著的抑制p<0.05)。T-2毒素激活JNK1后,信号通过JAK2传导,随后通过STAT3传递,其中IL-6和K-Ras在MAPK和JAK/STAT信号通路中发挥着纽带传递作用。阻断JNK1活性后,CIS、SOCS1和SOCS2基因显著上调表达(p<0.05),说明JNK1对此SOCS的3个亚家族进行负调控,但阻断JNK1后SOCS3基因下调,表明JNK1对SOCS3为正调控关系。
RAW264.7细胞中T-2毒素诱导后,JNK1信号经JAK2、STAT3、ERK和p38传导,激活的JAK2、STAT3、ERK和p38基因又可调控JNK1基因表达。阻断STAT3表达后,T-2毒素诱导的IL-6基因在12h受到显著抑制(p<0.05)。综合研究结果,IL-6激活JAK2/STAT3通路后,STAT3又可继续激活IL-6后续基因表达,进入下一循环,继续发挥作用。
经T-2毒素诱导后JNK1蛋白迅速磷酸化,并在1h开始转入细胞核内,随后会从核内返回胞质,但仍会继续进入核内。T-2毒素引起的p-JNK1穿梭入核至少持续12h。阻断JNK1活性后,STAT3磷酸化和入核均受到抑制,但STAT1未受影响。表明RAW264.7细胞中,T-2毒素诱导的STAT3磷酸化和入核发挥功能均受JNK1调控。
透射电镜观测结果显示,RAW264.7细胞与T-2毒素(14nM)孵育12h后,内质网扩张、线粒体肿大、核质边缘化,表明细胞出现了凋亡症状。28nMT-2毒素作用细胞12h后,核质完全边缘化,内质网扩张甚至形成空泡,线粒体肿胀,粗面内质网上核糖体出现脱粒,出现严重凋亡症状。观测结果表明T-2毒素主要作用于核糖体和线粒体。
阻断JNK1表达后,线粒体出现了明显肿胀,细胞凋亡率显著上升,基因Bcl-2/Bax和Bcl-xL/Bax比值均出现显著下降p<0.05),Caspase-3和Caspase-9基因水平显著上调,凋亡数据进一步验证了细胞超显微结构病变,表明JNK1具有保护RAW264.7细胞线粒体功能。阻断STAT3活性后,Bcl-2/Bax和Bcl-xL/Bax比值也出现明显下调p<0.05),进一步证明JNK1-STAT3为一条细胞保护通路,此通路可能通过保护线粒体的正常功能来抑制T-2毒素诱导的细胞凋亡。另一方面,本研究也证明T-2毒素是一把双刃剑,具有两面性,这一点也进一步丰富了对T-2毒素细胞毒性机理的认识。
液相质谱检测结果显示,在12h时细胞内T-2毒素含量显著高于2h时的含量。电镜超显微结构也观测到12h时细胞受损比2h时更加严重,表明T-2毒素长时间接触RAW264.7细胞,对其产生更高的毒性。2h后检测到的代谢物有HT-2毒素和3’-OH-T-2毒素,12h为3’-OH-T-2毒素,但含量甚低,T-2毒素始终是细胞内主要的毒性物质。
RAW264.7细胞中T-2毒素刺激后,MAPK和JAK/STAT信号通路之间存在错综复杂的交联转导关系。本研究揭示了IL-6和K-Ras在连接MAPK和JAK/STAT信号转导中发挥重要功能。[NK1-STAT3信号通路受T-2毒素刺激后发挥了保护线粒体,抑制细胞凋亡的功能。T-2毒素激活凋亡通路的同时,也能激活细胞的保护通路,抑制细胞的凋亡。T-2毒素靶向性损害RAW264.7细胞的线粒体和核糖体。T-2毒素进入细胞后,虽被代谢成多种物质,但T-2毒素仍占主导地位调控信号转导。
综上所述,本文首先研究了T-2毒素在肝脏和盲肠中的代谢,阐明了T-2毒素在不同种属动物中的代谢途径和特点,鉴定出5种主要代谢产物,充分完善了T-2毒素的代谢机制,对T-2毒素的残留监控及残留标示物的确定具有重要的指导意义。T-2毒素诱导下MAPK和JAK/STAT信号通路交联转导关系研究,进一步揭示了T-2毒素的毒性机制,为毒素防控、疾病预防、癌症治疗和新药开发提供了重要参考。
As one of the primary members of type-A trichothecenes, T-2toxin is produced mainly by Fusarium genus. T-2toxin is the greatest toxic one for animals among trichothecenes, and it could contamiant cereals such as wheat, barley, oats, and maize. T-2toxin is making a great harmful on animals and humans through feed contaimination. Importantly, T-2toxin could also inhibit the sysnthesis of protein, DNA and RNA through conjugating with ribosomes as well as the damage of mitochondria. This toxin could also activate MAPK and JAK/STAT signaling pathways as well as cytokine expression and induce cell apoptosis and immune dysfunction.
Metabolism of T-2toxoin has a close relationship with its toxicities. HT-2toxin,3'-OH-T-2, and neosolaniol (NEO) are the major metabolites of T-2toixn in animals. The toxicities change greatly once T-2toxin is biotransformed into different productes. The toxicity of most metabolites such as NEO and T-2triol are decreased. However, the toxicities of some metabolites such as3'-OH-T-2, are not decreased significantly, or even display a slightly higher toxicity. Thus, elucidation of the metabolic pathways and identifying the major metabolites of T-2toxin in animals are prerequisite to reveal its toxicity in animals, and are also crucial for food safety and human health. However, up to date, a global metabolism of T-2toxin in food producing animals is still unclear; especially the metabolic profiles are never compared in different species.
T-2toxin can cause damage on ribosomes and mitochondria and ultimately lead to cell apoptosis. MAPK signaling pathway is proved to be an important toxicological pathway of trichothecenes and plays critical roles in toxicity. T-2toxin can active this pathway rapidly and transiently. It is known that animals are normally exposed to trichothecenes slowly. The effects of inflammatory cytokines on cells are performed slowly and continually. For example, IL-6, IL-1β, and TNF-a were found to be activated after12h by trichothecenes in RAW264.7cells. MAPK is proved to be an important target signaling pathway of trichothecenes and could be activated in a rapid and transient way. Thus, a contradiction rises when trying to explain the rapid MAPK activation but slow activation of inflammatory factors. We suspect that some other signal pathways might exist at the downstream to transmit the signals from MAPKs and activate the inflammatory factors. Indeed, it is already proved from our previous work that JAK/STAT pathway are the downstream targets of trichothecenes and played important roles in regulation of proinflammatory cytokines as well as apoptosis. However, the upstream and downstream interrelationship between MAPK and JAK/STAT signal pathways is still unclear. Where do they peform their fuctions once they are activated, in nucleus or cytoplasm? What are the messengers to connect the two pathways and transmite the signals? All these questions need to be answered.
It is already known that T-2toxin can be well biotransformed in liver and intestine. Thus, we aimed to study the metabolism of T-2toxin in hepatic subcellular fractions (microsomes and cytosol) of pigs, chickens, rats, and carp (common carp and grass carp), as well as hepatocytes of rats, piglets and chickens. Based on the results, we discussed the metabolic difference of T-2toxin in different species. In addition, we also studied the degradation and metabolism of T-2toxin in pig cecum model. This study combined with the data in liver will further elucidate the metabolic fates of T-2toxin in animals. We also aim to study the cross talk between MAPK and JAK/STAT signaling pathways, which is induced by trichothecene T-2toxin. The cross talk between JNK1and STAT3were especially discussed. Specific inhibitors are useful tools to elucidate the signaling cross talk. In addition to the cross talk, we also monitored the typical ultrastructural changes of RAW264.7cells caused by T-2toxin and found out the potential toxicological targets of T-2toxin. The observation provides crucial visualized evidence for the molecular targets of trichothecenes. Finally, relationship between the toxic profiles and T-2toxin contents in intracellular in RAW264.7cells were also addressed. The results from this study will provide important data for explaning the sensitivity difference to T-2toxin in different animals, and is also important for identifying the residue markers as well as the prevention of disease. The study of signaling pathways will provide further information for the understanding of toxic mechanism of trichothecenes as well as the interrelationship between MAPK and JAK/STAT signaling pathways.
1. A comparation of hepatic metabolism of T-2toxin in pigs, chickens, carp and rats
Metabolic profiles of T-2toxin in the hepatocytes of food producing animals, pigs and chickens; rats-the major experimental model were compared. Metabolic pathways of T-2toxin in liver microsomes and cytosol of pigs, chickens, common carp, grass carp, and rats were also especially concerned. The metabolites were identified by HPLC-MS-IT-TOF.
In liver microsomes, five metabolites (MT1-5) were detected and identified. T-2toxin was mainly metabolized to HT-2toxin (MT1), neosolaniol (NEO)(MT2),3'-OH-T-2(MT3),3'-OH-HT-2(MT4), and T-2triol (MT5). T-2triol was only detectable in rat liver microsomes, implying that rat liver microsomes have stronger metabolic capability of T-2toxin than other species. In carp liver microsomes, HT-2toxin, NEO, and3'-OH-T-2were detected. Different with land animals, there was only trance amount of3'-OH-HT-2in carp liver microsomes. In grass carp,3'-OH-HT-2and3'-OH-HT-2, but not HT-2toxin were detected. The relative amount of HT-2toxin in land animals (pig, chicken, and rat) was much higher than that in carp (p<0.05). Hydrolysis to form HT-2toxin was the major metabolic pathway of T-2toxin in land animals (pig, chicken and rat). Different with land animals, HT-2toxin was not found in the liver microsomes of grass carp. In grass carp,3'-OH-T-2showed a relatively high amount, and followed with common carp. But in land animals, the capacity of transforming T-2toxin to3'-OH-T-2was relatively weak.
3'-OH-HT-2was not found in liver cytosol and the amount of3'-OH-T-2was also very low. Especially in common carp, the hydroxyl products were not found. Thus, we conclude that the hydroxyl capacity in liver cytosol is weaker than that in liver microsomes.
In hepatocytes, HT-2toxin and NEO were detectable. The amount of T-2toxin was much higher than NEO. Pigs produced a higher amount of HT-2toxin, chickens were the weakest. The hydroxyl products and C-8-deisovaleryl metabolites were not detected.
Taken together, there was a similarity in the metabolic pathways of T-2toxin among different species, but an interesting and different profile was also monitored. T-2toxin can be metabolized rapidly in liver. Hydrolysis (HT-2, NEO, and T-2triol) and hydroxylation (3'-OH-T-2and3'-OH-HT-2) were the major metabolic pathways in the liver from these species. Hydrolysis and forming HT-2toxin was the same pathway in these land animals. As compared with hydrolysis reaction, the hydroxylation was much weaker in land animals. But carp showed an opposite metabolic characteristic. HT-2, the very common metabolite in land animals, was rarely found in carp, but3'-OH-T-2was the major one. This result implies that the metabolism of T-2toxin in fish has some differences with land animals. The different characteristic of CYP450monooxygenase and carboxylesterase as well as the differece cataltic abilty in hydroxyaiton and hydrolysis actions by these enzymes between carp and land animals are possibly the reasons for the different metabolic profiles of T-2toxin. The findings of this study further improves the metabolic mechanism of T-2toxin and is also important for residue determination, residue marker identification as well as the toxic mechanism of trichothecenes.
2. Degradation and metabolism of T-2toxin in pig cecum model
To further provide the information of metabolism of T-2toxin in animals, a pig cecum model was produced to investigate the fate and degradation of T-2in animal intestines. The data combineding with liver metabolism will better uncover the metabolic pathways and bioavailbility of T-2toxin in animals.
T-2toxin was incubated with pig cecum at anaerobic conditions for20min,40min,1h,2h,4h,8h, and24h. Quercetin was used to monitor the activity of the bacterial in the pig cecum. The extraction of incubated samples was performed by a modified QuEChERS method. An Agilent1100series HPLC was linked to an API4000QTrap mass spectrometer. Heated Electrospray Ionization (HESI) coupled with a Thermo HPLC system was used to detect the potential metabolites.
Four different cecums were analyzed in comparison to the sterilized control. The degradation by the microbiota in Cecum1-3was much slower compared to Cecum4. In Cecum1-3, the degradation ranged31.1-45.9%of the originally incubated amount of T-2toxin. Only a small increase of the degradation between8and24h incubation time was detectable, e.g., only0.8%of T-2toxin was further degraded between8and24h in Cecum1. However, a very strong degradation was observed in Cecum4. About26±0.6%of T-2toxin were left after incubation for8h. Only3.0±0.1%of T-2toxin was detectable after24h.
Besides HT-2toxin, other metabolites, such as deepoxy-HT-2, were not detected. In Cecum4, the formed HT-2toxin was not further metabolized after a further incubation for8h. However, the relatively low recovery after24h incubation might indicate that HT-2toxin was possibly further metabolized to other products to an extent which was lower than the LOD of the HPLC-MS/MS equipment. Thus, we suspect that the toxic effects of T-2toxin in pigs are possibly afforded by the combination of T-2toxin and HT-2toxin.
In conclusion, T-2toxin is metabolized to HT-2toxin as the main metabolite by the intestinal microbiota of pigs with large interindividual difference. In one out of four analyzed cecums, T-2was nearly totally metabolized to HT-2toxin, whereas the other three cecums showed a degradation of T-2toxin up to46%. Besides HT-2toxin, no other metabolites were detectable in the incubated samples. For toxicity evaluations of T-2toxin in pigs, the combination of T-2and its major metabolite HT-2has to be considered, as both compounds show a similar cytotoxicity and absorption. The dagradation and metabolism study of T-2toxin in pig cecum further complemented the data of liver metaboism of T-2toxin and enriched the enterohepatic metabolic information; it also provides important references for the in vivo metabolism and toxic mechanism of T-2toxin.
3. The cross talk between MAPK and JAK/STAT signaling pathways induced by T-2toxin in RAW264.7cells
In order to study the cross talk between MAPK and JAK/STAT signaling pathway which is induced by T-2toxin, T-2toxin was incubated with RAW264.7cells for indicated time and the interrelationship between JNK, ERK, p38MAPK and JAK, STAT were investigated using the specific inhibitors. Furthermore, we studied the potential messengers between the two pathways. Besides the cross talk, we also monitored the typical ultrastructural changes of RAW264.7cells, which was caused by T-2toxin, and found out the potential toxicological targets of T-2toxin. This observation provides crucial visualized evidence for the molecular targets of trichothecenes. Moreover, the function of JNK1and STAT3were discussed using the inhibitors, immunoflourenscence and flow cytomery. Finally, the link between the toxic profiles and intracellular T-2toxin contents were addressed.
Results showed that the genes of ERK, JNK1and p38MAPK were activated within1-2h. However, they ceased quickly, implying that MAPK is a rapid signaling pathway. JAK2and STAT3mRNA were up regulated significantly, but they were slow and the highest peak was observed at12h. It is very possible that JAK/STAT pathway is the downstream singling of MAPK. IL-6among the studied cytokines showed the relatively highest up-regulation level, which was up regulated30.43-fold at2h and48.47-fold at12h. Thus, we suspected that IL-6possibly plays a very important role in the cross talk between MAPK and JAK/STAT signaling pathways. In addition, K-Ras had an important function in the cross talking, the up regulation after1and12h implying that K-Ras also plays roles in connecting the cross talk between MAPK and JAK/STAT.
In order to study the up-and down stream relationships, we used the specific inhibitors and monitored the gene levels and protein phosphorylation. When JNK1gene expression was blocked by its inhibitor SP600125, both the mRNA expression and protein phosphorylation of JAK2, and K-Ras response to T-2toxin were significantly suppressed. The gene expression and protein phosphorylation of STAT3, but not STAT1were significantly decreased. Interestingly, the gene expression of IL-6induced by T-2toxin was suppressed by SP600125at12h but not at2h. These results implies that the activated signals induced by T-2toxin could transfer from JNK1to JAK2/STAT3. Talk from JNK1to STAT3was possibly connected by IL-6. SOCS family is an important negatively regulator of JAK/STAT signaling pathway, we studied the relationships between JNK1and SOCS1,2,3, and CIS through blocking JNK1activity and found out that the mRNA expressions of CIS, SOCS1, and SOCS2were increased significantly, whereas the mRNA expression of SOCS3was decreased markedly. This observation implies that JNK1could regulate CIS, SOCS1, and SOCS2negatively, but positively regulate SOCS3.
Once induced by T-2toxin, signal of JNK1could transmit to JAK2, STAT3, ERK, and p38. Moreover, these activated genes can reversely regulate JNK1activity. Blocking STAT3activity, IL-6gene expression at12was suppressed remarkedly. Thus, we suspected that STAT3would further activate IL-6after the activation of JAK2/STAT3by IL-6and join in the next circulations.
JNK1was phosphorylated rapidly and imported into the nucleus, but the nucleus translocation is in a dynamic way and will later export to cytoplasm. When JNK1activity was blocked, the phosphorylation and nucleus translocation of STAT3were inhibited, but STAT1was not affected. This observation implies that phosphorylation and nucleus translocation of STAT3is JNK1-dependent.
When examined by transmission electron microscopy, mitochondrial swelling and the rough endoplasmic reticulum dilation were clearly visible when treated with T-2toxin at the level of14nM for12h. Once the toxin was increased to28nM, more serious morphological changes were observed. Besides the swelling mitochondria and the dilation of rough endoplasmic reticulum, polysomes on rough endoplasmic reticulum were also breakdown and degranulated. In addition, condensation and marginalization of chromatin aggregation were also monitored, which suggests that cells are induced to apoptosis by T-2toxin.
Interestingly, when the gene expression of JNK1was blocked, the apoptotic ratio was increased significantly than the blank or toxin treated group (p<0.05). This result demonstrates that JNK1induced by T-2toxin has an anti-apoptotic function in RAW264.7cells. The ratios of Bcl-xL/Bax and Bcl-2/Bax were both decreased after blocking JNK1or STAT3activity. The mRNA expression of Caspase-3and Caspas-9were markedly increased (p<0.05) when blocking JNK1and STAT3activities. These results further prove that the apoptosis induced by T-2toxin is a mitochondria-dependent caspase pathway. JNK1-STAT3pathway could inhibit apoptosis and its function is very possibly mediated by regulating the function of mitochondria. JNK1-STAT3is newly proved to be a cell survival pathway, and T-2toxin is shown to have a Janus face. This study adds to our further understanding of the toxic mechanism of trichothecenes.
Finally, the intracellular content of T-2toxin in different time points was detected. The content of T-2toxin was increased significantly at12h than at2h, indicating that intracellular content of T-2toxin can be accumulated with time increase. Moreover, T-2toxin can be biotransformed to HT-2toxin and3'-OH-T-2toxin at2h, whereas3'-OH-T-2toxin was the sole metabolite at12h in RAW264.7cells. But at the two time points, T-2toxin was the major product to perform the toxic effects and induced gene expression.
Taken together, a complicated cross talk between MAPK and JAK/STAT signaling pathways mediated by T-2toxin is reported for the first time. K-Ras and IL-6are proved to be critical messengers for the cross talk between JNK1and STAT3. Importantly, T-2toxin has a Janus face, which not only induces cell apoptosis, cell survival/defense pathways, such as JNK1-STAT3, could also be activated simultaneously. However, the cell defense signaling is possibly not strong and was swamped in the cell death signals, which makes it easily to be ignored. On the other hand, this study also reveals that cells could up regulate some defense signaling pathways when they are exposed to dangerous environment. This work also showes that ribosome and mitochondria are two major toxic targets of T-2toxin. The findings add to our further understanding of the toxic mechanisms of trichothecenes and the cross talk between MAPK and JAK/STAT signaling.
In summary, we first investigated the metabolism of T-2toxin in liver and intestine, and dentified5metabolites as well as the major metabolic pathways, also the metabolic profiles in different speices were compared. This study consummated the metabolic mechanism of T-2toxin, and provided crucial information for residue mornitoring and determination of residue marker of T-2toxin. The cross talk between MAPK and JAK/STAT signaling pathway further uncovered the toxic mechanism of T-2toxin and provide an important referece for toxin controlling, disease prevention, cancer treatment and drug development.
引文
柳芹.JAK/STAT信号通路在DON和T-2毒素对RAW264.7细胞毒性作用中的机制研究.[硕士学位论文].武汉：华中农业大学图书馆,2011.
Accensi F, Pinton P, Callu P, Abella-Bourges N, Guelfi JF, Grosjean F, Oswald IP. Ingestion of low doses of deoxynivalenol does not affect hematological, biochemical, or immune responses of piglets. Journal of Animal Science, 2006, 84:1935-1942.
Adachi M, Fukuda M, Nishida E. Two co-existing mechanisms for nuclear import of MAP kinase:passive diffusion of a monomer and active transport of a dimer. European Molecular Biology Organization, 1999, 18:5347-5358.
Ademoyero AA, Hamilton PB. Mouth lesions in broiler chickens caused by scirpenol mycotoxins. Poultry Science, 1991,70:2082-2089.
Albarenque SM, Doi K. T-2 toxin-induced apoptosis in rat keratinocyte primary cultures. Experimental and Molecular Pathology, 2005,78:144-149.
Alexopoulos C. Association of Fusarium mycotoxicosis with failure in applying an induction of parturition program with PGF2 alpha and oxytocin in sows. Theriogenology, 2001,55:1745-1757.
Anastassiades M, Lehotay SJ, Stajnbaher D, Schenck FJ. Fast and easy multiresidue method employing acetonitrile extraction/partitioning and'dispersive solid phase extraction'for the determination of pesticide residues in produce. Int Journal of AOAC International,2003,86:412-431.
Anderson DW, Black RM, Lee CG, Pottage C, Rickard RL, Sandford MS, Webber TD, Williams NE. Structure-activity studies of trichothecenes:cytotoxicity of analogues and reaction products derivied from T-2 toxin and neosolaniol. Journal of Medicinal Chemistry, 1989, 32:555-562.
Appeldoorn MM. Vincken JP, Aura A M, Hollman PC, Gruppen H. Procyanidin dimers are metabolized by humanmicrobiota with 2-(3,4-dihydroxy-phenyl) acetic acid and 5-(3,4-dihydroxyphenyl)-y-valerolactone as the major metabolites. Journal of Agricultural and Food Chemistry, 2009, 57(3):1084-1092.
Arunachalam C, Doohan FM. Trichothecene toxicity in eukaryotes:Cellular and molecular mechanisms in plants and animals. Toxicology Letters, 2013, 217: 149-158.
Avantaggiato G, Havenaar R, Visconti A. Assessing the zearalenone binding activity of adsorbent materials during passage through a dynamic in vitro gatrointestinal model, Food Chemical Toxicology, 2003,41:1283-1290.
Awad WA, Aschenbach JR, Setyabudi FMCS, Razzazi-Fazeli E, Bohm J, Zentek J. In vitro effects of deoxynivalenol on small intestinal d-glucose uptake and absorption of deoxynivalenol across the isolated jejunal epithelium of laying hens. Poultry Science,2007,86:15-20.
Babich, H, Borenfreund, E. Cytotoxicity of T-2 toxin and its metabolites determined with the neutral red cell viability assay. Applied and Environmental Microbiology, 1991, 57(7):2101-2103.
Bae, H, Gray, JS, Li, M, Vines, L, Kim, J, Pestka, JJ. Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. Toxicological Sciences, 2010, 115: 444-452.
Balogh K, Heincinger M, Fodor J, Mezes M. Effect of long term feeding of T-2 and HT-2 toxin contaminated diet on the glutathione redox status and lipid peroxidation processes in common carp (Cyprinus carpio L.). Acta Biologica Szegediensis, 2009, 53:23-27.
Barron MG, Charron KA, Stott WT, Duvall SE. Tissue carboxylesterase activity of rainbow trout. Environmental Toxicology and Chemistry, 1999, 18:2506-2511.
Bauer J. Wertmer R, Gedek B. Zur Kontamination von Futtermitteln mit toxinbildenen Fusarienstammen und deren Toxinen. Wiener tieraztliche Monatsschrift, 1980, 67: 282-288.
Bauer J, Bollwahn W, Gareis M, Gedek B, Heinritzi K. Kinetic profiles of diacetoxyscirpenol and two of its metabolits in blod serum of pigs. Applied and Environmental Microbiology, 1985,49: 842-845.
Bauer J. The metabolism of trichothecenes in swine. Deutshce Tierarztliche Wochenschrift, 1995,102(1):50-52.
Bayliss MK, Bell JA, Jenner WN, Park GR, BWilsonoe K. Utility of hepatocytes to model species differences in the metabolism of loxtidine and to predict pharmacokinetic parameters in rat, dog and man. Xenobiotica, 1999, 29:253-268.
Beasley VR, Swanson SP, Corley RA, Buck WB, Koritz G D, Burmeister H R. Pharmacokinetics of the trichothecene mycotoxin, T-2 toxin, in swine and cattle. Toxicon, 1986,24(1):13-23.
Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proceedings of the National Academy of Sciences of the United States of America, 2001,98(24):13681-13686.
Bennett JW, Klich M. Mycotoxins. Clinical Microbiology Reviews, 2003,16(3): 497-516.
Bensassi F, Gallerne C, Sharaf El Dein O, Lemaire C, Hajlaoui MR, Bacha H. Involvement of mitochondria-mediated apoptosis in deoxynivalenol cytotoxicity. Food and Chemical Toxicology, 2012,50(5):1680-1689.
Bergmann F, Soffer D, Yagen, B. Cerebral toxicity of the trichothecene toxin T-2, of the products of its hydrolysis and of some related toxins. Toxicon, 1988,26(10): 923-930.
Bergmann F, Yagen B. Structure-activity relationships for the direct toxic action of richothecenes on rat brain. Archives of Toxicology, 1989, 63:155-156.
Berthiller F, Dall'Asta C, Schumacher R, Lemmens M, Adam G, Krska R. Masked mycotoxins:Determination of a deoxynivalenol glucoside in artificially and naturally contaminated wheat by liquid chromatography-tandem mass spectrometry. Journal of Agricultural and Food Chemistry, 2005,53:3421-3425.
Berthiller F, Sulyok M, Krska R, Schuhmacher R. Chromatographic methods for the simultaneous determination of mycotoxin conjugates in cereals. International Journal of Food Microbiology, 2007, 119:33-37.
Betina V. Structure-activity relationships among mycotoxins. Chemico-Biological Interactions,1989,71:105-146.
Beyer M, Ferse I, Humpf HU. Large-scale production of selected type A trichothecenes: the use of HT-2 toxin and T-2 triol as precursors for the synthesis of d3-T-2 and d3-HT-2 toxin. Mycotoxin Research, 2009, 25:41-52.
Biehl ML, Prelusky DB, Koritz GD, Hartin KE, Buck B, Trenholm HL. Biliary excretion and enterohepatic cycling of zearalenone in immature pigs. Toxicology and Applied Pharmacology, 1993,121(1):152-159.
Bigalke H, Rummel A. Medical aspects of toxin weapons. Toxicology, 2005,214(3): 210-220.
Bin-Umer MA, McLaughlin JE, Basu D, McCormick S, Turner NE. Trichothecene mycotoxins inhibit mitochondrial translation-Implication for the mechanism of toxicity. Toxins, 2011, 3: 1484-1501.
Bondy GS, Pestka JJ. Immunomodulation by fungal toxins. Journal of Toxicology and Environmental Health, Part B,2000,3:109-143.
Borutova R, Faix S, Placha I, Gresakova L, Cobanova K, Leng L. Effects of deoxynivalenol and zearalenone on oxidative stress and blood phagocytic activity in broilers. Archives of Animal Nutrition, 2008,62(4):303-312.
Bouaziz C, Martel C, Sharaf el dein O, Abid-Essefi S, Brenner C, Lemaire C, Bacha H. Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis. Toxicological Sciences, 2009, 110(2): 363-375.
Bouhet S, Oswald IP. The intestine as a possible target for fumonisin toxicity. Molecule Nutrition and Food Reseach, 2007, 51:925-931.
Brase S, Encinas A, Keck J, Nising CF. Chemistry and biology of mycotoxins and related fungal metabolites. Chemical Reviews, 2009, 109: 3903-3990.
Buhler DR, Rasmusson ME. The oxidation of drugs by fishes. Comparative Biochemistry and Physiology, 1968, 25:223-239.
Buhler DR, Wang-Buhler JL. Rainbow trout cytochrome P450s: purification, molecular aspects, metabolic activity, induction and role in environmental monitoring. Comparative Biochemistry and Physiology Part C, 1998, 121:107-137.
Busby WFJr, Wogan GN. Trichothecenes. In: Mycotoxins and N-Nitroso Compounds: Environmental Risks; Shank, R.C, Ed, Fla: CRC Press. Boca Raton, 1981, pp.29-41.
Busman M, Poling SM, Maragos CM. Observation of T-2 toxin and HT-2 toxin glucosides from Fusarium sporotrichioides by Liquid Chromatography Coupled to Tandem Mass Spectrometry (LC-MS/MS). Toxins, 2011,3(12):1554-1568.
Butterfield L, Storey B, Maas L, Heasley LE. c-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation. Journal of Biological Chemistry, 1997, 272:10110-10116.
Caldwell J. Conjugation reaction in foreign-compound metabolism: definition, consequences, and species variations. Drug Metabolism Reviews, 1982, 13(5): 745-777.
Campbell S, Khosravi-Far R, Rossman K, Clark G, Der C. Increasing complexity of Ras signaling. Oncogene, 1998, 17: 1395-1413.
Carlson DB, Williams DE, Spitsbergen JM, Ross RF, Bacon CW, Meredith FI, Riley RT. Fumonisin B1 promotes aflatoxin B1 and N-methyl-N'- nitrosoguanidine-initiated liver tumors in rainbow trout. Toxicology and Applied Pharmacology, 2001,172: 29-36.
Carter BC, Cannon M. Structural requirement for the inhibitory action of 12,13-epoxytrichothecenes on protein synthesis in eukaryotes. Biochemical Journal, 1977,166:399-409.
Chanh TC, Hewetson, JF. Structure/function studies of T-2 toxin mycotoxin with a monoclonal antibody. Immunopharmacology, 1991,21: 83-90.
Chatterjee K, Viscontl A, Mirocha C J. Deepoxy T-2 teraol:a metabolite of T-2 toxin found in cow urine. Journal of Agricultural and Food Chemistry, 1986, 34(4): 695-697.
Chaudhari M, Jayaraj R, Bhaskar ASB, P.V. Lakshmana Rao PV. Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells. Toxicology, 2009, 262:153-161.
Chi MS, Robison TS, Mirocha CJ. Reddy KR. Acute toxicity of 12,13-expoxytrichothecenes in one-day-old broiler chicks. Applied and Environmental Microbiology, 1978,35(4):636-640.
Chi MS, Mirocha CJ, Kurtz HJ, Weaver G, Bates F, Shimoda W, Burmeister HR. Acute toxicity of T-2 toxin in broiler chicks and laying hens. Poultry Science, 1997, 56: 103-116.
Choi SU, Choi EJ, Kim HK, Kim NY, Kwon BM, Kim SU, Bok SH, Lee SY, Lee CO. Cytotoxicity of Trichothecenes to Human Solid Tumor Cells in Vitro. Archives of Pharmacal Research,1996,19(1):6-11.
Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and-independent pathways negatively modulates its Tyrosine phosphorylation. Molecular and Cellular Biology, 1997, 17(11):6508-6516.
Cimica V, Chen HC, Iyer JK, Reich NC. Dynamics of the STAT3 Transcription Factor: Nuclear Import Dependent on Ran and Importin-b1. PLoS One, 2011,6(5):1-11.
Coddington KA, Swanson SP, Hassan AS, Buck WB. Enterohepatic circulation of T-2 toxin metabolites in the rat. Drug Metabolism Disposition, 1989, 17:600-605.
Conkova E, Laciakova A, Kovac G, Seidel H. Fusarial toxins and their role in animal diseases. Veterinary Journal,2003,165(3):214-220.
Conrady-Lorck S, Gareis M, Feng XC, Amselgruber W, Forth W, Fichtl B. Metabolism of T-2 toxin in vascularly autoperfused jejunal loops of rats. Toxicology and Applied Pharmacology, 1988,94(1):23-33.
Coppock RW, Swanson SP, Gelberg HB. Preliminary study of the pharmacokinetics and toxicopathy of deoxynivalenol (vomitoxin) in swine. American Journal of Veterinary Reseach,1985,46(1):169-174.
Corley RA, Swanson SP, Buck, WB. Glucuronide conjugates of T-2 toxin and metabolites in swine bile and urine. Journal of Agricultural and Food Chemistry, 1985,33(6): 1085-1089.
Corley RA, Swanson SP Gullo GJ, Johnson L, Beasley VR, Buck WB. Disposition of T-2 toxin, a trichothecene mycotoxin, in intravascularly dosed swine. Journal of Agricultural and Food Chemistry, 1986, 34:868-875.
Costas I. Cytochrome P450 expression in the liver of food-producing animals. Current Drug Metabolism, 2006, 7(4):335-348.
Cote LM, Dahlem AM, Yoshizawa T, Swanson SP, Buck WB. Excretion of deox ynivalenol and its metabolite in milk, urine, and feces of lactating of dairy. Journal of Dairy Science, 1986, 69(9):2416-2423.
Cote LM, Buck W, Jeffery E. Lack of hepatic microsomal metabolism of deoxynivalenol and its metabolite DOM-1. Food and Chemical Toxicology, 1987, 25:291-295.
Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signaling pathway. Seminar in Cell & Development Biology, 2008,19:414-422.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Letters,1995,364(2): 229-233.
Cundliffe E, Cannon M, Davies J. Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins. Proceedings of the National Academy of Sciences,1974,71(1):30-34.
Cundliffe E, Davies JE. Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins. Antimicrobial Agents and Chemotherapy, 1977,11(3): 491-499.
D'Mello JPF, Placinta C M, Macdonald AMC. Fusarium mycotoxins: a review of global implications for animal health, welfare and productivity. Animal Feed Sciencei Technology, 1999, 80(3-4):183-205.
Danicke S, Ueberschar KH, Halle I, Valenta H, Flachowsky G. Excretion kinetics and metabolism of zearalenone in broilers in dependence on a detoxifying agent. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2001,55(4): 299-313.
Danicke S, Ueberschar KH, Halle I, Matthes S, Valenta H, Flachowsky G. Effect of addition of a detoxifying agent to laying hen diets containing uncontaminated or Fusarium toxin-contaminated maize on performance of hens and on carryover of zearalenone. Poultry Science, 2002, 84: 1671-1680.
Danicke S, Valenta H, Klobasa F, Doll S, Ganter M, Flachowsky G. Effects of graded levels of Fusarium toxin contaminated wheat in diets for fattening pigs on growth performance, nutrient digestibility, deoxynivalenol balance and clinical serum characteristics. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2004a, 58: 1-77.
Danicke S, Valenta H, Doll S. On the toxicokinetics and the metabolism of deoxynivalenol (DON) in the pig. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2004b, 58(2):169-180.
Danicke S, Goyarts T, Valenta H, Razzazi E, Boehm J. On the effects of deoxynivalenol (DON) in pig feed on growth performance, nutrients utilization and DON metabolism. Journal of Animal Feed Science,2004c,13(4):539-556.
Danicke S, Swiech E, Buraczewska, Ueberscha KH. Kinetics and metabolism of zearalenone in young female pigs. Journal of Animal Physiology and Animal Nutrition,2005,89:268-276.
David M, Grimley PM, Finbloom DS, Larner AC. A Nuclear Tyrosine phosphatase downregulates interferon-induced gene expression. Journal of Molecular Cell Biology, 1993,13(12):7515-7521.
De Boevre M, Diana Di Mavungu J, Landschoot S, Audenaert K, Eeckhout M, Maene P, Haesaert G, De Saeger S. Natural occurrence of mycotoxins and their masked forms in food and feed products. World Mycotoxin Journal, 2012, 5(3):207-219.
Desjardins AE, McCormick SP, Appell M. Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay. Journal of Agricultural and Food Chemistry, 2007, 55:6487-6492.
Desjardins AE. From Yellow rain to green wheat:25 years of trichothecene biosynthesis research. Journal of Agricultural and Food Chemistry, 2009, 57:4478-4484.
Dohnal V, Jezkova A, Jun D, Kuca K. Metabolic pathways of T-2 toxin. Current Drug Metabolism,2008,9:77-82.
Doi K, Ishigami N, Sehata S. T-2 Toxin-induced toxicity in pregnant mice and rats. International Journal of Molecular Sciences,2008,9(11):2146-2158.
Doll S, Danicke S, Schnurrbusch U. The effect of increasing concentrations of Fusarium toxins in the diets of piglets on histological parameters of uterus. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003a, 19:73-76.
Doll S, Danicke S, Ueberschar K, Valenta H, Schnurrbusch U, Klobasa F, Flachowsky G. Effects of graded levels of Fusarium toxin contaminated maize in diets female weaned piglets. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003b, 23: 311-334.
Dol1 S, Schrickx JA, Valenta H, Danicke S, Fink-Gremmels J. Interactions of deoxynivalenol and lipopolysaccharides on cytotoxicity protein synthesis and metabolism of DON in porcine hepatocytes and Kupffer cell enriched hepatocyte cultures. Toxicological Letters, 2009, 189: 121-129.
Dombrink-Kurtzman MA, Javed T, Bennet GA, Richard JL, Cote LM, Buck WB. Lymphocyte cytotoxicity and erythrocyte abnormalities induced in broiler chicks by fumonisins B1 and B2 and moniliformin from Fusarium proliferatum Mycopathologia, 1994,124: 47-54.
Dombrink-Kurtzman MA, Dvorak TJ. Fumonisin content in masa and tortillas from Mexico. Journal of Agricultural Food Chemistry, 1999,47: 622-627.
EFSA. Scientific opinion on the risk from animal and public health related to the presence of T-2 and HT-2 toxin in food and feed. EFSA Journal, 2011,9: 2481.
Ehrlich KC, Daigle KW. Protein synthesis by mammalian cells treated with C-3-modified analogs of the 12, 13-epoxytrichothecenes T-2 and T-2 tetraol. Applied and Environmental Microbiology, 1985,50(4):914-918.
Ehrlich KC, Daigle KW. Protein synthesis inhibition by 8 oxo-12,13-epoxytrichothecenes. Biochimica et Biophysica Acta, 1987, 923:206-213.
Ember LR. Yellow rain. Chemical and Enginerring News, 1984, 9:8-34.
Engemann A, Hubner F, Rzeppa S, Humpf, HU. Intestinal metabolism of two A-type procyanidins using the pig cecum model: Detailed structure elucidation of unknown catabolites with fourier transform mass spectrometry (FTMS). Journal of Agricultural and Food Chemistry, 2012, 60(3):749-757.
English, BK, Ihle JN, Myracle A. Yi T. Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. Journal of Experimental Medicine,1993,178:1017-1020.
Eriksen GS, Pettersson H, Johnsen K, Lindberg JE. Transformation of trichothecenes in ileal digesta and faeces from pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2002, 56(4): 263-274.
Eriksen GS, Pettersson H, Lindberg J E. Absorption, metabolism and excretion of 3-acetyl DON in pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003,57(5):335-345.
Eriksen GS. Metabolism and Toxicity of Trichothecenes. (Ph.D dissertation). Swedish University of Agricultural Sciences:Uppsala, 2003.
Eriksen GS, Pettersson H, Lundh T. Comparative cytotoxicity of deoxynivalenol, nivalenol, their acetylated derivatives and de-epoxy metabolites. Food and Chemical Toxicology, 2004, 42:619-624.
Eriksen GS, Pettersson, H. Toxicological evaluation of trichothecenes in animal feed. Animal Feed Science and Technology, 2004, 114(1-4):205-239.
European Commission 2006. Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. Official Journal the European Union L364:5-24.
Fang H, Wu Y, Guo J, Rong J, Ma L, Zhao Z, Zuo D, Peng S. T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway. Apoptosis, 2012, 17:895-907.
Fink-Gremmels J, Malekinejad H. Clinical effects and biochemical mechanisms associated with exposure to the mycoestrogen zearalenone. Animal Feed Science and Technology, 2007, 137(3-4):326-341.
Fodor J, Meyer K, Riedlberger M, Bauer J, Horn P, Kovacs F, Kovacs M. Distribution and elimination of fumonisin analogues in weaned piglets after oral administration of Fusarium verticillioides fungal culture. Food Additives and Contaminants, 2006, 23: 492-501.
Fodor J, Meyer K, Gottschalk C, Mamet R, Kametler L, Bauer J, Horn P, Kovacs F, Kovacs M. In vitro microbial metabolism of fumonisin B-1. Food Additives and Contaminants,2007,24(4):416-420.
Fodor J, Balogh K, Weber M, Mezes M, Kametler L, Posa R, Mamet R, Bauer J, Horn P, Kovacs F, Kovacs M. Absorption, distribution and elimination of fumonisin B1 metabolites in weaned piglets. Food Additives & Contaminants Part A, 2008,25: 88-96.
Fornelli F, Minervini F, Mule G. Cytotoxicity induced by nivalenol, deoxynivalenol, and fumonisin B, in the SF-9 insect cell line. In Vitro Cellular & Developmental Biology, 2004,40(56):166-171.
Forsell J, Kateley J.R, Yoshizawa T, Pestka J. Inhibition of mitogen-induced blastogenesis in human lymphocytes by T-2 toxin and its metabolites. Applied and Environmental Microbiology, 1985,49(6):1523-1526.
Fuchs, E, Binde EMr, Heidler D, Krska R. Structural characterization of metabolites after the microbial degradation of type A trichothecenes by the bacterial strain BBSH 797. Food Additives & Contaminants,2002,19(4):379-386.
Fukuda, M, Gotoh, I, Gotoh, Y, and Nishida E. Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal. Journal of Biological Chemistry, 1996, 271:20024-20028.
Furuno T, Hirashima N, Onizawa S, Sagiya N, Nakanishi M. Nuclear shuttling of Mitogen-Activated Protein (MAP) kinase (Extracellular signal-Regulated Kinase (ERK2) was dynamically controlled by MAP/ERK Kinase after antigen stimulation in RBL-2H3 cells. Journal of Immunology, 2001,166: 4416-4421.
Galaverna G, DallAsta C, Mangia M, Dossena A, Marchelli R. Masked mycotoxins an emergingissue for food safety. Czech Journal of Food Sciences, 2009, 27:89-92.
Galhardo M, Birgel EH, Soares LMV, Furalani RPZ. Poisoning by diacetoxyscirpenol in cattle fed citrus pulp in the state of Sao Paulo, Brazil. Brazilian Journal of Veterinary Research and Animal Science,1997,34:90-91.
Garaleviciene D, Pettersson H, Elwinger K. Effects on health and blood plasma parameters of laying hens by pure nivalenol in the diet. Journal of Animal Physiology and Nimal nutrition, 2002,86(11-12):389-398.
Gardiner SA, Boddu J, Berthiller F, Hametner C, Stupar RM, Adam G, Muehlbauer GJ. Transcriptome analysis of the barley-deoxynivalenol interaction: evidence for a role of glutathione in deoxynivalenol detoxification. Molecular Plant-microbe Interactions, 2010,23(7):962-976.
Ge X, Wang J, Liu J, Jiang J, Lin H, Wu J, Ouyang M, Tang X, Zheng M, Liao M, Deng Y. The catalytic activity of cytochrome P450 3A22 is critical for the metabolism of T-2 toxin in porcine reservoirs. Catalysis Communications, 2010, 12(2): 71-75.
Gelderblom W C, Jaskiewicz K, Marasas W F, Thiel PG, Horak RM, Vleggaar R, Kriek NP. Fumonisins-novel mycotoxins with cancer promoting activity produced by Fusarium moniliforme. Applied and Environmental Microbiology, 1988, 54: 1806-1811.
Gelderblom WC, Kriek NP, Marasas WF, Thiel PG. Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1 in rats. Carcinogenesis, 1991,12: 1247-1251.
Gelderblom WC, Marasas WF, Vleggaar R, Thiel PG, Cawood ME. Fumonisins: isolation, chemical characterization and biological effects. Mycopathologia, 1992, 117:11-16.
Glavitis R, Vanyi A. More important mycotoxicosis in pigs. Magyar Allatorvosak Lapja, 1995,50: 407-420.
Glenn AE. Mycotoxigenic Fusarium species in animal feed. Animal Feed Science and Technology, 2007,137(3-4):213-240.
Glickman AH, Hamid AAR, Rickert DE, Lech AJ. Elimination and metabolism of permethrin isomers in rainbow trout. Toxicology and Applied Pharmacology, 1981, 57: 88-98.
Glickman AH, Lech JJ. Hydrolysis of permethrin, a pyrethroid insecticide, by rainbow trout and mouse tissues in vitro:a comparative study. Toxicology and Applied Pharmacology, 1981,60:186-192.
Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced Translocation of Mitogen-activated Protein Kinase to the cell surface ruffling membrane and the nucleus. Journal of Molecular Cell Biology, 1993,122(5): 1089-1101.
Gorina R, Petegnief V, Chamorro A, Planas A M. AG490 prevents cell death after exposure of rat astrocytes to hydrogen peroxide or proinflammatory cytokines: involvement of the Jak2/STAT pathway. Journal of Neurochemistry, 2005, 92: 505-518.
Groc L, Bezin, L, Jiang, H, Jackson T, Levine RA. Bax, Bcl-2 and cyclin expression and apoptosis in rat substantia nigra during development. Neuroscience letters 2001, 306(3):198-202.
Grove JF, Mortimer PH. The cytotoxicity of some transformation products of diacetoxyscirpenol. Biochemical Pharmacology, 1969,18:1473-1478.
Grove JF, Hosken M. The larvicidal activity of some 12,13-epoxytrichothece-9-enes. Biochemical Pharmacology, 1975, 24:959-962.
Guan S, He J, Young C, Zhu H, Li XZ, Ji C, Zhou T. Transformation of trichothecene mycotoxins by microorganisms from fish digesta. Aquaculture, 2009, 290:290-295.
Gutleb AC, Morrison E, Albertina JM. Cytotoxicity assays for mycotoxins produced by Fusarium strains: a review. Environmental Toxicology and Pharmacology, 2002, 11: 309-320.
He CH, Fan YH, Wang Y, Huang CY, Wang XC, Zhang HB. The individual and combined effects of deoxynivalenol and aflatoxin B1 on primary hepatocytes of cyprinus carpio. International Journal of Molecular Sciences, 2010, 11:3760-3768.
He P, Young GL, Forsberg C. Microbial transformation of Deoxynivalenol (vomitoxin). Applied and Environmental Microbiology, 1992, 58(12):3857-3863.
Hedman R, Thuvander A, Gadhasson I, Reverter M, Pettersson H. Influence of dietary nivalenol exposure on gross pathology and selected immunological parameters in young pigs. Natural Toxins, 1997a, 5(6): 238-246.
Hedman R, Pettersson H, Lindberg J E. Absorption and metabolism of nivalenol in pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 1997b, 50(1):13-24.
Hedman R, Pettersson H. Transformation of nivalenol by gastrointestinal microbes. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 1997, 50(4): 321-329.
Hein EM, Rose K, van't Slot G, Friedrich AW, Humpf HU. Deconjugation and degradation of flavonol glycosides by pig cecal microbiota characterized by fluorescence in situ hybridization (FISH). Journal of Agricultural and Food Chemistry, 2008, 56(6): 2281-2290.
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochemical Journal, 1998,334: 297-314.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal,2003,374:1-20.
Hendry KM, Cole EC. A review of mycotoxins in indoor air. Journal of Toxicology and Environmental Health,1993,38:183-198.
Hestbjerg H, Nielsen KF, Thrane U, Elmholt S. Production of trichothecenes and other secondary metabolites by Fusarium culmorum and Fusarium equiseti on common laboratory media and a soil organic matter agar: an ecological interpretation. Journal of Agriculture and Food Chemistry, 2002, 50:7593-7599.
Hibi M, Lin A, Smeal T, Minden A, and Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes & Development, 1993,7:2135-2148.
Hinoshita F. Nivalenol and human kidney disease? Nephron, 1997, 75:469.
Hodge DR, Hurt EM, Farrar WL:The role of IL-6 and STAT3 in inflammation and cancer. The European Journal of Cancer, 2005, 41:2502-2512.
Holstege CP, Bechtel LK, Reilly TH, Wispelwey BP, Dobmeier SG Unusual but potential agents of terrorists. Emergency Medicine Clinics of North America, 2007, 25: 549-552.
Hoyt R, Zhu W, Cerignoli F, Alonso A, Mustelin T, David M. Cutting edge: selective Tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase. Journal of Immunology, 2007, 179:3402-3406.
Huff WE, Doerr JA, Hamilton PB, Vesonder RF. Acute toxicity of vomitoxin (deoxynivalenol) in broiler chickens. Poultry Sci, 1981,60:1412-1414.
Humpf H,U, Voss KA. Effects of food processing on the chemical structure and toxicity of fumonisin mycotoxins. Molecular Nutrition & Food Research, 2004, 48:255-269.
Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends in Genetics,1995,11(2):69-74.
Inoue M, M orikawa M, Tsubio M, Sugiura M. Species difference and characterization of intestinal esterase on the hydrolyzing activity of ester-type drugs. Japanese Journal of Pharmacology, 1979, 29:9-16.
Ikawa M, Carr C, Tatsuno T. Trichothecene structure and toxicity to the green alaga Chlorella Pyrenoidosa. Toxicon, 1985,23(3):535-537.
Islam Z, Nagase M, Ota A, Ueda S, Yoshizawa T, Sakato N. Structure-function relationship of T-2 toxin and its metabolites in inducing thymic apoptosis in vivo in mice. Bioscience, Biotechnology, and Biochemistry, 1998,62(8):1492-1497.
James LJ, Smith TK. Effect of dietary alfalfa on zearalenone toxicity and metabolism in rats and swine. Journal of Animal Science,1982,55:110-118.
Jarvis BB, Eppley RM, Mazolla EP. Chemistry and bioproduction of macrocyclic trichothecenes. In: Ueno Y, ed. Trichothecenes-Chemical, Biological and Toxicological Aspects, Amsterdam:Elsevier, 1983:20-38.
Jaaro H, Rubinfeld H, Hanoch T, Seger R. Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation. Proceedings of the National Academy of Sciences of the United States of America. 1997,94, 3742-3747.
JECFA. Deoxynivalenol. Joint FAO/WHO Expert Committee on Food Additives, 56th report. Safety evaluation of certain mycotoxins in food. WHO Food Additives Series 47, Geneva, Switzerland: WHO,419-556. 2001a. Online at: www.inchem.org/documents/ jecfa/jecmono/v47je05.htm. Accessed on Aug 06, 2013.
JECFA. T-2 and HT-2. Joint FAO/WHO Expert Committee on Food Additives, 56th report. Safety evaluation of certain mycotoxins in food. WHO Food Additives Series 47, Geneva, Switzerland: WHO,419-556. 2001b. Online at: www.inchem.org/documents/jecfa/jecmono/v47je06. htm. Accessed on Aug 06, 2013.
JECFA. Zearalenone. In: Joint FAO/WHO Expert Committee on Food Additives ed. Safety evaluation of certain food additives and contaminants. WHO/FAO Food additives Series 44. IPCS-International Programme on Chemical Safety. 2000, WHO, Geneva: FAO Food and Nutrition Paper, 2006. 1-778.
Jeker N, Tamm C. Synthesis of new unnatural macrocyclic trichothecenes: 4-epiverrucarin A. Helvetica Chimica Acta, 1988, 71:1904-1913.
Jimenez M, Mateo R. Determination of mycotoxins produced by Fusarium isolates from banana fruits by capillary gas chromatography and high-performance liquid chromatography. Journal of Chromatography A, 1997, 778:363-372.
Joffe AZ. Toxicity of Fusarium poae and F. sporotrichoides and its relation to alimentary toxic aleukia. In: Purchase IFH ed., Mycotoxins. Amsterdam: Elsevier, Amsterdam, 1974.229-262.
Joffe AZ. On the question of yellow rain. In: Joffe AZ ed., Fusarium Species: Their Biology and Toxicology. Wiley, New York: 1986. 441-444.
Johnsen H, Odden E, Lie O, Johnese BA, Fonnum F. Metabolism of T-2 toxin by rat liver carboxylesterase. Biochemical Pharmacology, 1986, 35:1469-1473.
Johnsen H, Odden E, Johnsen BA, Fonnum F. Metabolism of T-2 toxin by blood cell carboxylesterases. Biochemical Pharmacology, 1988, 37(16):3193-3197.
Kaplan DH, Shankaran V, Dighe AS, Stoker E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon gdependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences, 1998, 95:7556-7561.
Karlovsky. P. Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives. Applied Microbiology and Biotechnology, 2011,91:491-504.
Katz R, Singer B. Can an attribution assessment be made for Yellow Rain? Systematic reanalysis in a chemical-and-biological-weapons use investigation. Politics and the Life Sciences,2007,26(1):24-42.
Kemppainen, BW, Riley, RT, Pace, JQ Hoerr, FJ, Joyave, J. Evaluation of monkey skin as a model for in vitro percutaneous penetration and metabolism of [3H]T-2 toxin in human skin. Fundamental and Applied Toxicology, 1986a, 7:367-375.
Kemppainen BW, Riley RT, Pace, JQ Hoerr, FJ. Effects of skin storage conditions and concentration of applied dose on [3H]T-2 toxin penetration through excised human and monkey skin. Food and Chemical Toxicology, 1986b, 24(3):221-227.
Kennedy DG, Hewitt SA, McEvoy JD, Currie JW, Cannavan A, Blanchflower WJ, Elliot CT. Zeranol is formed from Fusarium spp. toxins in cattle in vivo. Food Additives and Contaminants,1998, 15:393-400.
Kennedy NJ, Sluss HK, Jones SN, Bar-Sagi D, Flavell RA, Davis RJ. Suppression of Ras-stimiluated transformation by the JNK signal transduction pathway. Genes & Development, 2003,17:629-637.
Keppler K, Humpf HU. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorganic & Medicinal Chemistry letters, 2005,13:5195-5205.
Keppler K, Hein EM, Humpf, HU. Metabolism of quercetin and rutin by the pig caecal microflora prepared by freeze-preservation. Moloculer Nutrition and Food Research, 2006,50:686-695.
Kiessling KH, Pettersson H, Sandholm K, Olsen M. Metabolism of aflatoxin, ochratoxin, zearalenone, and three trichothecenes by intact rumen fluid, rumen protozoa, and rumen Bacteria. Applied and Environmental Microbiology, 1984, 47(5):1070-1073.
Kiessling KH. Biochemical mechanism of action of mycotoxins. Pure and Applied Chemistry, 1986, 58(2):327-338.
Kimura M, Kaneko I, Komiyama M, Takatsuki A, Koshino H, Yoneyama K, Yamaguchi I. Trichothecene 3-Oacetyltransferase protects both the producing organism and transformed yeast from related mycotoxins. Cloning and characterization of Tri101. Journal of Biological Chemistry, 1998,273:1654-1661.
King RS. Biotransformations in Drug Metabolism. In: Nassar AF, Hollenberg PF, Scatina J eds., Drug metabolism handbook: Concepts and applications. Hoboken, UAS:John Wiley & Sons; 2009.17-41.
Kleinova M, Zollner P, Kahlbacher H, Hochsteiner W, Lindner W. Metabolic profiles of the mycotoxin zearalenone and of the growth promoter zeranol in urine, liver, and muscle of heifers. Journal of Agriculture and Food Chemistry, 2002,50:769-4776.
Knupp CA, Swanson SP, Buck WB. In vitro metabolism of T-2 toxin by rat liver microsomes. Journal of Agricultural and Food Chemistry, 1986, 34:865-868.
Knupp CA, Swanson SP, Buck WB. Comparative in vitro metabolism of T-2 toxin by hepatic micrsomes prepared from phenobarbital-induced or control rats, mice, rabbits and chickens. Food and Chemical Toxicology, 1987a, 25:859-865.
Knupp CA, Corley DG, Tempessta MS, Swanson SP. Isolation and characterization of 4'-hydroxy T-2 toxin, a new metabolite of the trichothecene mycotoxin T-2. Drug Metabolism and Disposition,1987b, 15(6): 816-820.
Kobayashi J, Horikoshi T, Ryu JC, Tashiro F, Ishii K, Ueno Y. The cytochrome P-450-dependent hydroxylation of T-2 toxin in various animal species. Food and Chemical Toxicology,1987,25(7): 539-544.
Kollarczik B, Gareis M, Hanelt M. In vitro transformation of the Fusarium mycotoxins, deoxynivalenol and zearalenone, by the normal gut microflora of pigs. Journal of Natural Toxins,1994,2: 105-110.
Konigs M, Mulac D, Schwerdt G, Gekle M, Humpf HU. Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture. Toxicology, 2009, 258:106-115.
Kravchenko LV, Galash VT, Avren'eva LT, Kranauskas AE. On the sensitivity of carp, Cyprinus carpio, to mycotoxin T-2. Journal of Applied Ichthyology, 1989, 29: 156-160.
Krishnaswamy R, Devaraj SN, Padma VV. Lutein protects HT-29 cells against Deoxynivalenol-induced oxidative stress and apoptosis:prevention of NF-kappaB nuclear localization and down regulation of NF-kappaB and Cyclo-Oxygenase-2 expression. Free Radical Biology and Medicine,2010,49(1):50-60.
Kruber P, Trump S, Behrens J, Lehmann I. T-2 toxin is a cytochrome P450 1A1 inducer and leads to MAPK/p38- but not aryl hydrocarbon receptor-dependent interleukin-8 secretion in the human intestinal epithelial cell line Caco-2. Toxicology,2011,284: 34-41.
Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA. The jnkl and jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 1999, 22:667-676.
Kubena LF, Edrington, TS, Harvey, RB, Phillips TD, Sarr AB, Rottinghaus GE. Individual and combined effects of fumonisin B1 present in Fusarium moniliforme culture material and diacetoxyscirpenol or ochratoxin A in turkey poults. Poultry Science,1997,76:256-264.
Kuca K, Pohanka M. Chemical warfare agents. Mol Clin Environ Toxicol, 2010, 100: 543-58.
Kuiper-Goodman T, Scott P M, Watanabe H. Risk assessment of the mycotoxin zearalenone. Regulatory Toxicology and Pharmacology, 1987, 7: 253-306.
Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science, 1997, 278:1630-1632.
Labib S, Hummel S, Richling E, Humpf HU, Schreier P. Use of the pig caecum model to mimic the human intestinal metabolism of hispidulin and related compounds. Molecular Nutrition & Food Research,2006,50:78-86.
Lake BG, Phillips JC, Waters DG, Bayley DL, Cook MW, Thomas LV, Gilbert J, Startin JR, Baldwin NCP, Bycroft BW, Dewick PM. Studies on the metabolism of deoxynivalenol in the rat. Food and Chemical Toxicology, 1987, 25(8):589-592.
Lancova K, Hajslova J, Poustka J, Krplova A, Zachariasova M, Dostalek P, Sachambula L. Transfer of Fusarium mycotoixns and masked" deoxynivalenol (deoxynivalenol-3-glucoside) from field barely through malt to beer. Food Additives and Contaminants,2008,25:732-744.
Larsen J C, Hunt J, Perrin I, Ruckenbauer P. Workshop on trichothecenes with a focus on DON: summary report. Toxicology Letters, 2004, 153:1-22.
Laskin JD, Heck DE, Laskin DL. The ribotoxic stress response as a potencial mechanism for MAP Kinase activation in xenobiotic toxicity. Toxicological Sciences, 2002, 69: 298-291.
Lattanzio VM, Solfrizzo M, Visconti A. Enzymatic hydrolysis of T-2 toxin for the quantitative determination of total T-2 and HT-2 toxins in cereals. Analytical and Bioanalytical Chemistry, 2009,395:1325-1334.
Lattanzio VMT, Visconti A, Haidukowski M, Pascale M. Identification and characterization of new Fusarium masked mycotoxins, T2 and HT2 glycosyl derivatives, in naturally contaminated wheat and oats by liquid chromatography-high-resolution mass spectrometry. Journal of Mass Spectrometry, 2012,47:466-475.
Lavrijsen K, Houdt JV, Dyck DV, Hendrickx J, Bockx M, Hurkmans R, Meuldermans W, Jeune LL, Lauwers W, Heykants J. Comparative metabolism of flunarizine in rats, dogs and man: an in vitro study with subcellular liver fractions and isolated hepatocytes. Xenobiotica, 1992, 22:815-836.
Ledoux DR, Brown TP, Weibking TS, Rottinghaus GE. Fumonisin toxicity in broiler chicks. Journal of Veterinary Diagnostic Investigation, 1992, 4:330-333.
Lemke SL, Ottinger SE, Ake CL, Mayura K, Phillips TD. Deamination of fumonisin B1 and biological assessment of reaction product toxicity. Chemical Research in Toxicology, 2001,14:11-15.
Lenormand, P, Sardet, C, Pages, G, L'Allemain, G, Brunet A., Pouyssegur J. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. Journal of Cell Biology, 1993,122:1079-1088.
Lewis CW, Smith JE, Anderson JG, Freshney RI. Increased cytotoxicity of food-borne mycotoxins toward human cell lines in vitro via enhanced cytochrome p450 expression using the MTT bioassay. Mycopathologia, 1999, 148:97-102.
Li YC, Ledoux DR, Bermudez AJ, Fritsche KL, Rottinghaus GE. Effects of fumonisin B1 on selected immune responses in broiler chickens. Poultry Science,1999, 78: 1275-1282.
Li Y, Wang Z, Beier RC, Shen J, Smet DD, Saeger SD, Zhang S. T-2 Toxin, a trichothecene mycotoxin: review of toxicity, metabolism, and analytical methods. Journal of Agricultural and Food Chemistry, 2011,59: 3441-3453.
Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis. BioEssays, 2002, 25:17-24.
Li SN, Fan DF. Activity of esterases from different tissues of freshwater fish and responses of their isoenzymes to inhibitors. Journal of Toxicology and Environmental Health, 1997,51:149-157.
Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death. Cell,1996,87:565-576.
Liu J, Minemoto Y, Lin A. c-Jun N-Terminal Protein Kinase 1 (JNK1), but Not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Journal of Molecular Cell Biology, 2004,24(24): 10844-10856.
Liu ZY, Huang LL, Dai MH, Chen DM, Wang YL, Tao YF, Yuan ZH. Metabolism of qlaquindox in rat liver microsomes: structural elucidation of metabolites by high-performance liquid chromatography combined with ion trap/time-of-flight mass spectrometry. Rapid Comunications in Mass Sepctrometry, 2008, 22: 1009-1016.
Lun AK, Moran ETJ, Young L G, McMillan EG. Absorption and elimination of an oral dose of 3H-deoxynivalenol in colostomized and intact chickens. Bulletin Environmental Contamination and Toxicology, 1989, 42: 919-925.
Ma Y, Zhang A, Shi Z, He C, Ding J, Wang X, Mac J, Zhang H. A mitochondria-mediated apoptotic pathway induced by deoxynivalenol in human colon cancer cells. Toxicology in Vitro, 2012, 26: 414-420.
Madhyastha MS, Marquardt RR, Abramson D. Structure-activity relationships and interactions among trichothecene mycotoxins as assessed by yeast bioassay. Toxicon, 1994,32(9):1147-1152.
Mahadevan B, Marston CP, Luch A, Dashwood WM, Brooks E, Pereira C, Doehmer J, Baird WM. Competitive inhibition of carcinogen-activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar. International Journal of Cancer,2007,120:1161-1168.
Malaney S, Daly RJ. The Ras signaling pathway in mammary tumorigenesis and metastasis. Journal of Mammary Gland Biology and Neoplasia, 2001,6(1):101-113.
Malekinejad H, Maas-Bakker RF, Fink-Gremmels J. Bioactivation of zearalenone by porcine hepatic biotransformation. Veterinary Research, 2005,36(5-6):799-810.
Malekinejad H, Maas-Bakker R, Fink-Gremmels J. Species differences in the hepatic biotransformation of zearalenone. Veterinary Journal, 2006, 172:96-102.
Marasas WFO. Discovery and occurrence of the fumonisins:A historical perspective. Environ Health Perspect, 2001,109(Suppl. 2):239-243.
Marin S, Magan N, Serra J, Ramos A J, Canela R, Sanchis V. Fumonisin B1 production and growth of Fusarium moniliforme and Fusarium proliferatum on maize, wheat and barley grain. Journal of Food Science, 1999,64:921-924.
Mateo JJ, Mateo R, Jimenez M. Accumulation of type A trichothecenes in maize, wheat and rice by Fusarium sporotrichioides isolates under diverse culture conditions. International Journal of Food Microbiology, 2002, 72:115-123.
Mathur S, Constable PD, Eppley RM, Tumbleson ME, Smith GW, Tranquilli WJ, Morin D E, Haschek W M. Fumonisin B1 increases serum sphinganine concentrations but does not alter serum sphingosine concentration or induce cardiovascular changes in milk-fed calves. Toxicological Sciences, 2001,60:379-384.
McCormick SP. Fusarium head blight of wheat and barley. American Phytopathological Society, St. Paul, Minnesota, USA.2003.165-183
McKinney JD, Richard A, Waller C, Newman MC, Gerberick F. The practice of structure activity relationships (SAR) in toxicology. Toxicological Sciences, 2000, 56:8-17.
McLaughlin CS, Vaughan MH, Campbell IM, Wei CM, Stafford ME, Hansen B S. Inhibition of protein synthesis by tricho thecenes. In: Rodricks JV, Hesseltine CW, Mehlman MA eds. Mycotoxins in human and animal health. Park Forest South: Pathotox Publications,1977.261-284.
McLaughlin JE, Bin-Umer, MA, Tortora A, Mendez N, McCormick S, Turner NE. A genome-wide screen in Saccharomyces cerevisiae reveals a critical role for the mitochondria in the toxicity of a trichothecene mycotoxin. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(51): 21883-21888.
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathway:cross-talk and compensation. Trends in Biochemical Sciences, 2011,36(6):443-456.
Merrill AHJ, Sullards MC, Wang E, Voss KA, Riley RT.Sphingolipid metabolism:roles in signal transduction and disruption by fumonisins. Environmental Health Perspectives, 2001,109: 283-289.
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifinan CM. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature, 1996, 379: 645-648.
Middlebrook JL, Leatherman DL. Binding of T-2 toxin to eukaryotic cell ribosomes. Biochemical Pharmacology, 1989,38:3103-3110.
Miles CO, Erasmuson AF, Wilkins AL. Ovine metabolism of zearalenone to a-zearalanol (zeranol). Journal of Agriculture and Food Chemistry, 1996, 44:3244-3250.
Minervini F, Fornelli F, Flynn KM. Toxicity and apoptosis induced by the mycotoxinsnivalenol, deoxynivalenol and fumonisin B1 in a human erythroleukemia cell line. Toxicology in Vitro, 2004, 18:21-28.
Miranda CL, Wang JL, Henderson MC, Buhler DR. Purification and characterization of hepatic steroid hydroxylases from untreated rainbow trout. Archives of Biochemistry and Biophysics, 1989, 268(1):227-238.
Miranda CL, Wang JL, Henderson MC, Zhao X, Guengerich FP, Buhler DR. Comparison of rainbow trout and mammalian cytochrome P450 enzymes: evidence for structural similarity between trout P450 LMC5 and human P450ⅢA4. Biochemical and Biophysical Research Communications, 1991,176: 558-63.
Mirocha CJ, Pawlosky RA, Chatterjee K, Watson S, Hayes W. Analysis for Fusariun toxins in variol samples implicated in biological warfare in Southeast Asia. Journal of the Association of Official Analytical Chemists 1983,66(6): 1485-1499.
Mirocha CJ, Robison TS, Pawlosky RJ, Allen NK, Distribution and residue determination of [3H]zearalenone in broilers. Toxicology and Applied Pharmacology, 1982, 66: 77-87.
Mizuguchi R, Noto S, Yamada M, Ashizawa S, Higashi H, Hatakeyama M. Ras and signal transducer and activator of transcription (STAT) are essential and sufficient downstream components of Janus kinases in cell proliferation. Japanese Journal of Cancer Research, 2000,91(5):527-533.
Moon Y, Uzarski R, Pestka J.J. Relationship of trichothecene structure to COX-2 induction in the macrophage: selective action of type B (8-keto) trichothecenes. Journal of Toxicology and Environmental Health Part A, 2003,66:1967-1983.
Moss MO. Mycotoxin review-2. Fusarium. Mycologist, 2002,16:158-161.
Muehlbauer GJ, Boddu J, Gardiner S, Shin S, Jia H, Cho S, Mccormick S.P, Schweiger W, Lemmons M, Berthiller F, Hametner C, Kovalsky Paris PM, Torres-Acosta JA, Adam G. The role of trichothecenes in the Triticeae-Fusarium graminearum interactions. American Phytopathological Society, 2012.
Munger CE, Ivie GW, Christopher RJ, Hammock BD, Phillips TD. Acetylation/deacetylation reactions of T-2, acetyl T-2, HT-2, and acetyl HT-2 toxins in bovine rumen fluid in vitro. Journal of Agricultural and Food Chemistry, 1987, 35(5):354-358.
Nakagawa H, Ohmichi K, Sakamoto S, Sago Y, Kushiro M, Nagashima H, Yoshida M, Nakajima T. Detection of a news Fusarium masked mycotoxin in wheat grain by high-resolution LC-OrbitrapTM-MS. Food Additives and Contaminants, 2011,28(1): 1447-1456.
Nielsena KF, Thrane U. Fast methods for screening of trichothecenes in fungal cultures using gas chromatography-tandem mass spectrometry. Journal of Chromatography A, 2001,929: 75-87.
Novoa JRU, Diaz GJ. Aflatoxins and its mechanisms of toxicity in hepatic cancer. Revista Facultad de Medicina de la Universidad Nacional de Colombia, 2006, 54(2): 108-116.
Novotny WE, Dixit A. Pulmonary hemorrhage in an infant following 2 weeks of fungal exposure. Archives of Pediatrics& Adolescent medicine, 2000, 154: 271-275.
Ohta M, Ishii K, Ueno Y. Metabolism of trichothecene mycotoxins I. Journal of Cellular biochemistry, 1977, 82:1591-1598.
Ohta M, Matsumoto H, Ishii, K. Metabolism of trichothecene mycotoxins II. Journal of Biochemistry, 1978,84(3): 697-706.
Olsen M, Kiessling K H. Species differences in zearalenone-reducing activity in subcellular fractions of livers from female domestic animal species. Acta Pharmacological et Toxicolica, 1983,52:287-291.
Olsen M, Malmlof K, Pettersson H, Sandholm K, Kiessling KH. Plasma, urinary levels of zearalenone and alpha-zearalenol in a prepubertal gilt fed zearalenone. Acta Pharmacological et Toxicolica, 1985, 56:239-243.
Onji Y, Dohi Y, Aoki Y, Moriyama T, Nagami H, Uno M, Tanaka T, Yamazoe Y. Deepoxynivalenol: a new metabolite of nivalenol found in the excreta of orally administered rats. Journal of Agriculture and Food Chemistry, 1989, 37:478-481.
Parkinson A, Ogilvie BW. Biotransformation of xenbiotics. In Klaassen CD ed., Casarett and Doull's Toxicology-The Basic Science of Poisons (7th Edition):New York, USA: McGraw-Hill. 2008. 161-304.
Pace JG Metabolism and clearance of T-2 mycotoxin in perfused rat livers. Fundamental and Applied Toxicology, 1986, 7(3): 424-433.
Pawlosky RJ, Mirocha CJ. Structure of a metabolic derivative of T-2 toxin (TC-6) based on mass spectrometry. Journal of Agricultural and Food Chemistry, 1984, 32(6):1420-1423.
Pestka JJ, Tai JH, Witt MF, Dixon DE, Forsell JH. Suppression of immune response in the B6C3F1 mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone. Food Chemical and Toxicology, 1987, 25:297-304.
Pestka JJ, Yan D, King LE. Flow cytometric analysis of the effects of in vitro exposure to vomitoxin deoxynivalenol on apoptosis in murine T, B and IgA+ cells. Food and Chemical Toxicology, 1994, 32:1125-1136.
Pestka JJ. Deoxynivalenol: Toxicity, mechanisms and animal health risks. Animal Feed Science and Technology, 2007, 137: 283-298.
Pestka JJ. Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Additive and Contaminants, Part A. 2008,25(9):1128-1140.
Pestka JJ. Deoxynivalenol-induced proinflammatory gene expression: mechanisms and pathological sequelae. Toxins, 2010, 2(6):1300-1317.
Placinta CM, D'Mello JPF, Macdonald AMC. A review of worldwide contamination of cereal grains and animal feed with Fusarium mycotoxins. Animal Feed Science and Technology, 1999,78:21-37.
Poapolathep A, Sugita-Konishi Y, Doi K, Kumagai S. The fates of trichothecene mycotoxins, nivalenol and fusarenon-X, in mice. Toxicon, 2003, 41(8): 1047-1054.
Poapolathep A, Kumagai S, Suzuki H, Doi K. Development of early apoptosis and changes in T-cell subsets in mouse thymocyte primary cultures treated with nivalenol. Experimental and Molecular Pathology, 2004a, 77(2):149-152.
Poapolathep A, Sugita-Konishi Y, Phitsanu T, Doi K, Kumagai S. Placental and milk transmission of trichothecene mycotoxins, nivalenol and fusarenon-X, in mice. Toxicon,2004b,44(1):111-113.
Poapolathep A, Singhasem S, Noonpugdee C, Sugita-Konishi Y, Doi K, Kumagai S. The fate and transmission of Fusarenon-X (FX), a trichothecene mycotoxin in mice. Toxicology and Applied Pharmacology, 2004c, 197(3):367-367.
Pompa G, Montesissa C, Di Lauro FM, Fadini L. The metabolism of zearalenone in subcellular fractions from rabbit and hen hepatocytes and its estrogenic activity in rabbits. Toxicology 1986, 42(1):69-75.
Poppenberger B, Berthiller F, Lucyshyn D, Sieberer T, Schuhmacher R, Krska R, Kuchler K, Glossl J, Luschnig C, Adam G. Detoxification of the fusarium mycotoxin deoxynivalenol by a UDP-glucosyltransferase from Arabidopsis thaliana. Journal of Biological Chemistry, 2003,278(48):47905-47914.
Prelusky DB, Trenholm HL, Lawrence GA, Scott P M. Nontransmission of deoxynivalenol (vomitoxin) to milk following oral administration to dairy cows. Journal of Environmental Science and Health (B),1984, 19:593-609.
Prelusky DB, Veira DM. Trenholm HL. Plasma pharmacokinetics of the mycotoxin deoxynivalenol following oral and intravenous administration to sheep. Journal of Environmental Science and Health (B),1985,20(6):603-624.
Prelusky DB, Hamilton RM, Trenholm HL, Miller JD. Tissue distribution and excretion of radioactivity following administration of 14C-labeled deoxynivalenol to White Leghorn hens. Fundamental and Applied Toxicology, 1986a, 7(4):635-645.
Prelusky DB, Veira D M, Trenholm HL, Hartin KE. Excretion profiles of the mycotoxin deoxynivalenol, following oral and intravenous administration to sheep. Fundamental and Applied Toxicology, 1986b, 6(2):356-363.
Prelusky DB, Veira DM, Trenholm HL,Foster BC. Metabolic fate and elimination in milk, urine and bile of deoxynivalenol following administration to lactating sheep, Journal of Environmental Science and Health B,1987,22(2):125-148.
Prelusky DB, Hartin KE, Trenholm HL, Miller JD. Pharmacokinetic fate of 14C-labeled deoxynivalenol in pigs. Fundamental and Applied Toxicology, 1988,10:276-286.
Prelusky DB, Trenholm HL,Savard ME. Pharmacokinetic fate of 14C-labelled fumonisin B1 in swine. Natural Toxins, 1994, 2:73-80.
Prelusky DB, Savard ME, Trenholm HL. Pilot study on the plasma pharmacokinetics of fumonisin B1 cows following a single dose by oral gavage or intravenous administration. Natural Toxins,1995,3:389-394.
Prelusky DB, Mille JDr, Trenholm HL. Disposition of 14C-derived residues in tissues of pigs fed radiolabelled fumonisin B1. Food Additives and Contaminants, 1996a, 13: 155-162.
Prelusky DB, Trenholm HL, Rotter BA, Miller JD, Savard ME, Yeung JM, Scott PM. Biological fate of fumonisin B1 in food producing animals. Advances in Experimental Medicine and Biology, 1996b, 392:265-278.
Qing Y, Liang Y, Du Q, Fan P, Xu H, Xu Y, Shi N. Apoptosis induced by Trimethyltin chloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talk between NF-кB and MAPKs signaling pathways. Archives of Toxicology, 2013, 87(7):1273-1285.
Rafai P, Bata A, Vanyi A, Papp Z, brydl E, Jakab L, Tuboly S, Tury E. Effects of various levels of T-2 toxin on the clinical status, performance and metabolism of growing pigs. Veterinary Record, 1995a, 136: 485-489.
Rafai P, Tuboly S, Bata A, Tilly P, Vanyi A, Papp Z, Jakab L, Tury E. Effects of various levels of T-2 toxin in the immune system of growing system of growing pigs. Veterinary Record, 1995b,136:511-514.
Raisbeck MF, Rottinghaus GE, Kendall JD. Effects of naturally occurring mycotoxins on ruminants. In: Smith JE, Henderson RS eds., Mycotoxins in Animal Foods. Boca Raton: CRC Press,1991.647-677.
Regis G, Pensa S, Boselli D, Novelli F, Poli V. Ups and downs:the STAT1:STAT3 seesaw of interferon and gp130 receptor signaling. Seminars in Cell & Developmental Biology, 2008, 19: 351-359.
Remmer MDH. The role of the liver in drug metabolism. The American Journal of Medicine,1979, 49(5):617-625.
Rheeder JP, Marasas WFO, Vismer HF. Production of fumonisin analogs by Fusarium species. Applied and Environmental Microbiology, 2002, 68:2101-2105.
Riley RT, Enongene E, Voss KA, Norred WP, Meredith FI, Sharma RP, Spitsbergen J, Williams DE, Carlson DB, Merrill AHJ. Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environmental and Health Perspectives (Suppl.2), 2001,109: 301-308.
Robison TS, Mirocha CJ, Kurtz HJ, Behrens JC, Weaver GA, Chi MS. Distribution of tritium-labeled T-2 toxin in swine. Journal of Agricultural and Food Chemistry, 1979, 27:1411-1413.
Rocha O, Ansari K Doohan FM. Effects of trichothecene mycotoxins on eukaryotic cells: A review. Food Additives and Contaminants,2005,22:369-378.
Rosen RT, Rosen JD. Presence of four Fusarium mycotoxins and synthetic material in"yellow rain":Evidence for the use of chemical weapons in Laos. Biomedical Mass Spectrometry, 1982,9(10):443-450.
Rotblat B, Ehrlich M, Haklai R, Kloog Y. The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras:a potential treatment for cancer. Methods Enzymol, 2008,439:467-489.
Rotter B, Thompson BK, Clarkin S, Owen TC. Rapid colorimetric bioassay for screening of Fusarium mycotoxins. Natural Toxins, 1993,1:303-307.
Rotter BA, Prelusky DB, Pestka JJ. Toxicology of deoxynivalenol (vomitoxin). Journal of Toxicology and Environmental Health, Part A, 1996, 48:1-34.
Roybal JE, Munns RK, Morris WJ, Hurlbut JA, Shimoda W. Determination of zeranol /zearalenone and their metabolites in edible animal tissue by liquid chromatography with electrochemical detection and confirmation by gas chromatography/mass spectrometry. Journal of the Association of Official Analynical Chemists, 1988,71: 263-271.
Ryu D, Hanna MA. Eskridge KM and Bullerman LB, Heat stability of zearalenone in an aqueous buffered model system. Journal of Agriculture and Food Chemistry, 2003, 51:1746-1748.
Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF. Distinct role for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Molecular Cell Biology, 2004, 15(5):713-275.
Sakamoto T, Swanson SP, Yoshizawa T, Buck WB. Structures of new metabolites of diacetoxyscirpenol in the excreta of orally administered rats. Journal of Agricultural and Food Chemistry, 1986, 34:698-701.
Sakatsume M, Stancato LF, David M, Silvennoinen O, Saharinen P, Pierce J, Larner AC, Finbloom DS. Interferony activation of Raf-1 is Jakl-dependent and p21ras-independent. Journal of Biological Chemistry, 1998,273(5):3021-3026.
Satoh T, Hosokawa M. Carboxylesterases:structure, function and polymorphism. Biomolecules & Therapeutics,2009,17(4):335-347.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 1.Deoxynivalenol (DON),1-9.1999. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out44_en.pdf. Accessed on Aug on 06, 2013.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 4. Nivalenol. 2000-10-19. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out74_en.pdf. Accessed on Aug 06, 2013.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 5. T-2 toxin and HT-2 toxin. 2001-05-30. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out88_en.pdf. Accessed on Aug 06, 2013.
SCF (Scientific Committee on Food). Opinion of the Scientific Committee on Food on Fusarium toxins. Part 6: Group evaluation of T-2 toxin, HT-2 toxin, nivalenol and deoxynivalenol.2002. http://ec.europa.eu/food/fs/sc/scf/out123_en.pdf. Accessed on Aug 06, 2013.
Schoental R, Joffe AZ, Yagen B. Cardiovascular lesions and various tumors found in rats given T-2 Toxin, a trichothecene metabolite of fusarium. Cancer Reseacher, 1979, 39:2179-2189.
Schroeder JJ, Cousins R. Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocytemonolayer cultures. Proceedings of the National Academy of Sciences,1990,87:3134-3141.
Schuringa JJ, Jonk LJ, Dokter WH, Vellenga E, Kruijer W. Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components. Biochemical Journal, 2000, 1(347):89-96.
Schust J, Sperl B, Hollis A, Mayer T U, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chemistry & Biology, 2006, 13 (11):1235-1242.
Sekikawa A, Fukui H, Fujii S, Ichikawa K, Tomita S, Imura J, Chiba T, Fujimori T. REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. Carcinogenesis, 2008, 29:76-83.
Senter LH, Sanson DR, Corley DG, Tempesta MS, Rottinghaus AA, Rottinghaus GE. Cytotoxicity of trichothecene mycotoxins isolated from Fusarium sporotrichioides (MC-72083) and Fusarium sambucinum in baby hamster kidney (BHK-21) cells. Mycopathologia, 1991,13(2):127-131.
Sergent T, Parys M, Garsou S, Pussemier L, Schneider YJ, Larondelle Y. Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicology Letters, 2006, 164:167-176.
Sewald N, von Gleissenthall JL, Schuster M, Muller G, Aplin RT. Structure elucidation of a plant metabolite of 4-desoxynivalenol. Tetrahedron Asymmetry, 1992,3(7): 953-960.
Shang S, Jiang J, Deng Y. Chicken cytochrome P4501A5 is the key enzyme for metabolizing T-2 Toxin to 3'-OH-T-2. International Journal of Molecular Sciences, 2013,14(6):10809-10818.
Shanghyun S, Antonio T.A, Franz B, Wolfgang S, Gerhard A, Susan M, Gary M. Identifying and characterizing barley genes that protect against trichothecene mycotoxins. Poster. American Society of Plant Biologists, 2011.
Shank RA, Foroud NA, Hazendonk P, Eudes F, Blackwell BA. Current and future experimental strategies for structural analysis of trichothecene mycotoxins-a prospectus. Toxins, 2011,3:1518-1553.
Shephard GS, Thiel PG, Sydenham EW, Vleggaar R, Alberts JF. Determination of the mycotoxin fumonisin B1 and identification of its partially hydrolysed metabolites in the faeces of non-human primates. Food and Chemical Toxicology, 1994, 32:23-29.
Shepard GS, Thiel PG. Sydenham EW, Snijman PW, Toxicokinetics of fumonisin B2 in rats. Food and Chemical Toxicology, 1995,33:591-595.
Shi Y, Porter K, Parameswaran N, Bae HK, Pestka JJ. Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced Interleukin-6 upregulation in the macrophage. Toxicological Sciences, 2009, 109(2):247-255.
Shier WT, Shier AC, Xie W, Mirocha CJ. Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins. Toxicon, 2001,39:1435-1438.
Shifrin VI, Andreson P. Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. Journal of Biological Chemistry, 1999, 274:13985-13992.
Shima J, Takase S, Takahashi Y, Iwai Y, Fujimoto H, Yamazaki M, Ochi K. Novel detoxification of the trichothecene mycotoxin deoxynivalenol by a soil bacterium isolated by enrichment culture. Applied and Environmental Microbiology, 1997, 63: 3825-3830.
Shreeve BJ, Patterson DS, Pand Roberts BA. The carry-over of aflatoxin, ochratoxin and zearalenone from naturally contaminated feed to tissues, urine and milk of dairy cows. Food and Cosmetetic Toxicology, 1979,17:51-152.
Sintov A, Bialer M, Yagen B. Pharmacokinetics of T-2 toxin and its metabolite HT-2 toxin, after intravenous administration in dogs. Drug metabolism and disposition, 1986, 14(2):250-254.
Sintov A, Bialer M, Yagen B. Pharmacokinetics of T-2 tetraol, a urinary metabolite of the trichothecene mycotoxin, T-2 toxin in dog. Xenobiotica, 1987, 17(8): 941-950.
Smith TK. Recent advances in the understanding of Fusarium trichothecene mycotoxicoses. Journal of Animal Science, 1992, 70: 3989-3993.
Smith J, Thakur R. Occurrence and fate of fumonisins in beef. In: Jackson L ed., Fumonisins in Food. New York: Plenum Press, 1996. 39-55.
So EY, Oh J, Jang JY, Kim JH, Lee CE. Ras/Erk pathway positively regulates Jakl/STAT6 activity and IL-4 gene expression in Jurkat T cells. Molecular Immunology, 2007, 44(13):3416-3426.
Soriano JM, Dragacci S. Occurrence of fumonisins in foods. Food Research International, 2004,37: 985-1000.
Stegeman JJ. Cytochrome P450 forms in fish: catalytic, immunological and sequence similarities. Xenobiotica, 1989,19:1093-1110.
Stephanou A, Latchman DS. Opposing actions of STAT-1 and STAT-3. Growth Factors, 2005,23(3):177-182.
Sudakin, DL. Trichothecenes in the environment: relevance to human health. Toxicology Letters,2003,143:97-107.
Swanson SP, Nicoletti J, Rood HDJ, Buck WB, Cote LM. Metabolism of three trichothecene mycotoxins, T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by bovine rumen microorganisms. Journal of Chromatography-Biomedical Application, 1987a, 414: 335-342.
Swanson SP, Rood H D J, Behrens JC, Sanders AE. Preparation and Characterization of the Deepoxy Trichothecenes: Deepoxy HT-2, Deepoxy T-2 Triol, Deepoxy T-2 Tetraol, Deepoxy 15-Monoacetoxyscirpenol and Deepoxy Scirpentriol. Applied and Environment Microbiology, 1987b, 153(12): 2821-2826.
Swanson SP, Helaszek C, Buck WB, Rood HDJr, Haschek WM. The role of intestinal microflora in the metabolism of trichothecene mycotoxins. Food and Chemical Toxicology, 1988, 26(10):823-829.
Sydenham EW, Stockenstrom S, Thiel PG, Shepard GS, Koch KR, Marasas WFO. Potential of alkaline hydrolysis for the removal of fumonisins from contaminated corn. Journal of Agriculture and Food Chemistry,1995,43:1198-1201.
Sypecka Z, Kelly M, Brereton P. Deoxynivalenol and zearalenone residues in eggs of laying hens fed with a naturally contaminated diet: Effects on egg production and estimation of transmission rates from feed to eggs. Journal of Agriculture and Food Chemistry, 2004, 52(17):5463-5471.
Tang G, Minemoto Y, Dibling N, Purcell NH, Li M. Inhibition of JNK activation through NF-кB target genes. Nature, 2001,414:313-317.
Thibaut R, Schnell S, Porte C. The interference of pharmaceuticals with endogenous and xenobiotic metabolizing enzymes in carp liver: an in-vitro study. Environmental Science & Technology, 2006,40:5154-5160.
Thomas S. Refinement of the coomassie blue method of protein quantitation. A simple and linear spectrophotometric assay for less than or equal to 0.5 to 50 microgram of protein. Analytical Biochemistry, 1978,86(1):142-146.
Thompson W.L, Wannemacher RWJr. Structure-function relationships of 12,13-expoxytrichothecene mycotoxins in cell culture:comparation to whole animal lethality. Toxicon, 1986, 24(10):985-994.
Thompson WL, Wannemacher RWJr. In vivo effects of T-2 mycotoxin on synthesis of proteins and DNA in rat tissues. Toxicology and Applied Pharmacology, 1990, 105(3):482-491.
Tiemann U, Brussow KP, Kuchenmeister U, Jonas L, Pohland R, Reischauer A, Jager K, Danicke S. Changes in the spleen and liver of pregnant sows and full-term piglets after feeding diets naturally contaminated with deoxynivalenol and zearalenone. Veterinary Journal, 2008,176(2):188-196.
Trebstein A, Lauber U, Humpf HU. Analysis of Fusarium toxins via HPLC-MS/MS multimethods:Matrix effects and strategies for compensation. Mycotoxin Research, 2009,25:201-213.
Trenerry MK, Carey KA, Ward AC, Cameron-Smith D. STAT3 signaling is activated in human skeletal muscle following acute resistance exercise. Journal of Applied Physics, 2007, 102:1483-1489.
Trenholm HL, Friend DW, Hamilton RMG, Thompson BK, Hartin KE. Incedence and toxicology of deoxynivalenol as an emerging mycotoxin problem. Proc VI International Conf on the Mycoses, 1986, Pan Amercian Health Organization, Washington, DC.
Trusal LR, O'Brien JC, Ultrastructural effects of T-2 mycotoxin on rat hepatocytes in vitro. Toxicon,1986,24(5):481-488.
Trusal LR. Metabolism of T-2 mycotoxin by cultured cells. Toxicon, 1986, 24:597-603.
Tsygankov AY, Shore SK. Src: regulation, role in human carcinogenesis and pharmacological inhibitors. Current Pharmaceutical Design, 2004, 10: 1745-1756.
Tucker, JB. The "yellow rain" controversy: Lessons for arms control compliance. Nonproliferation Review, 2001,8:25-42.
Turker L, Gumus S. Quantum chemical treatment of nivalenol and its tautomers. Journal of Hazardous Materia, 2008,153:329-339.
Ueno Y, Hosoya M, Morita Y, Ueno I, Tatsuno, T. Inhibition of the protein synthesis in rabbit reticulocyte by Nivalenol, a toxic principle isolated from Fusarium nivale-growing rice. Journal of Biological Chemistry, 1968, 64(4): 479-485.
Ueno Y, Nakajima M, Sakal K, Ishii K, Sato N, Shimada N. Comparative toxicology of trichothece mycotoxins: inhibiton of protein synthesis in animal cells. Journal of Biochemistry, 1973,74: 285-296.
Ueno Y. Trichothecenes: overview address. In: Rodricks JV, Hesseltine CW, Mehlman MA eds., Mycotoxins in Human and Animal Health. Park Forest South, Illinois, USA: Phathotox Publishers. 1977. 189-207.
Ueno Y, Toxicological features of T-2 toxin and related trichothecenes. Fundamental and Applied Toxicology, 1984, 4: S124-S132.
Ueno Y. Trichothecene mycotoxins: Mycology, chemistry, and toxicology. Advances in Food & Nutrition Research,1989,3:301-353.
Usleber E, Renz V, Martbauer E, Terplan G. Studies on the application of enzyme immunoassays for the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and zearalenone. Zentralbl Veterinarmed B,1992,39:617-627.
van't Slot G, Humpf HU. Degradation and metabolism of catechin, epigallocatechin-3-gallate (EGCG), and related compounds by the intestinal microbiota in the pig cecum model. Journal of Agricultural and Food Chemistry, 2009,57:8041-8048.
van't Slot G, Mattern W, Rzeppa S, Grewe D, Humpf HU. Complex flavonoids in cocoa: synthesis and degradation by intestinal microbiota. Journal of Agricultural and Food Chemistry, 2010, 58:8879-8886.
Vanyi A, GIvatis R, Gajdacs E, Sandor G, Kovacs F. Changes in newborn piglets by the trichothecene toxin T-2. Acta Veterinaria Hungarica, 1991,39: 29-37.
Vetter IR, Arndt A, Kutay U, Gorlich D, Wittinghofer A. Structural view of the Ran-Importin beta interaction at 2.3 A resolution. Cell, 1999, 97:635-646.
Visconti A, Mirocha CJ. Identification of various T-2 Toxin metabolites in chicken excreta and tissues. Applied and Environment Microbiology, 1985, 49(5): 1246-1250.
Volotinen M, Turpeinen M, Tolonen A, Uusitalo J, Maenpaa J, Pelkonen. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metabolism and Disposition, 2007, 35(7):1135-1141.
Voss KA, Norred WP, Meredith FI, Riley RT, Saunders DS. Fumonisin concentration and ceramide synthase inhibitory activity of corn, masa, and tortilla chips. Journal of Toxicology and Environmental Health, 2006, 69:1387-1397.
Voss KA, Smith GW, Haschek WM. Fumonisins: Toxicokinetics, mechanism of action and toxicity. Animal Feed Sciencei Technology, 2007, 137(3-4):299-325.
Voyksner RD, Hagler WMJr, Swanson SS. Analysis of some metabolites of T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by thermospray high-performance liquid chromatography-mass spectrometry. Journal of Chromatography, 1987, 394: 183-199.
Vudathula DK, Prelusky DB, Ayroud M, Trenholm HL, Miller JD.Pharmacokinetic fate and pathological effects of 14C-fumonisin B1 in laying hens. Natural Toxins, 1994, 2: 81-88.
Wang E, Ross FP, Wilson TW, Riley RT, Merrill AHJ. Increases in serum sphingosine and sphinganine and decreases in complex sphingolipids in ponies given feed containing fumonisins, mycotoxins produced by Fusarium moniliforme. Journal of Nutrition,1992,122:1706-1716.
Wang J, Jiang J, Zhang H, Wang J, Cai H, Li C, Li K, Liu J, Guo X, Zou G, Wang D, Deng Y, Dai J. Integrated transcriptional and proteomic analysis with in vitro biochemical assay reveal the important role of CYP3A46 in T-2 toxin hydroxylation in porcine primary hepatocytes. Molecular & Cellular Proteomics, 2011,10(9): M111.008748.
Wang X, Liu Q, Ihsan A, Huang L, Dai M, Hao H, Cheng G, Liu Z, Wang Y, Yuan Z. JAK/STAT pathway plays a critical role in the proinflammatory gene expression and apoptosis of RAW264.7 cells induced by trichothecenes as DON and T-2 toxin. Toxicological Sciences, 2012, 127(2):412-424.
Wannenmacher RW, Wiener SL. Trichothecene Mycotoxins. In:Sidell FR, Takafuji ET, Franz DR, eds. Medical aspects of chemical and biological warfare. Washington, DC, USA:Office of the Surgeon General at TMM Publications, 1997:655-676.
Webster KA., Discher DJ, Bishopric, NH. Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. Journal of Biological Chemistry, 1993,268:16852-16858.
Wei CM, McLaughlin CS. Structure-function relationship in the 12, 13-expoxytrichothecenes-Novel inhibitors of protein synthesis. Biochemical and Biophysical Research Communications, 1974, 57(3):838-844.
Wu J, Jing L, Yuan H, Peng SQ. T-2 toxin induce apoptosis in ovarian granulosa cells of rats through reactive oxygen species-mediated mitochondrial pathway. Toxicology Letters,2011c,202:168-177.
Weidner M, Welsch T, Hiibner F, Humpf HU. Identification and apoptotic potential of T-2 Toxin metabolites in human cells. Journal of Agricultural and Food Chemistry, 2012, 60: 5676-5684.
Welsch T, Humpf HU. HT-2 Toxin 4-Glucuronide as new T-2 toxin metabolite: enzymatic synthesis, analysis, and species specific formation of T-2 and HT-2 toxin glucuronides by rat, mouse, pig, andhuman liver microsomes. Journal of Agricultural and Food Chemistry, 2012, 60: 10170-10178.
Wen Z, Zhong Z, Darnell JEJr. Maximal activation of transcription by Statl and Stat3 requires both tyrosine and serine phosphorylation. Cell, 1995, 82:241-250.
Wu Q, Dohnal V, Huang L, Kuca K, Yuan Z. Metabolic pathways of trichothecenes. Drug Metabolism. Reviews,2010,42(2):250-267.
Wu Q, Huang L, Liu Z, Yao M, Wang Y, Dai M, Yuan Z. A comparison of hepatic in vitro metabolism of T-2 toxin in rats, pigs, chickens, and carp. Xenobiotica, 2011a, 41(10):863-873.
Wu Q, Lohrey L, Cramer B, Yuan Z, Humpf HU. Impact of physicochemical parameters on decomposition of deoxynivalenol during extrusion cooking of wheat grits. Journal of Agricultural and Food Chemistry, 2011b, 59(23): 12480-12485.
Wu Q, Engemann A, Cramer B, Welsch T, Yuan Z, Humpf HU. Intestinal metabolism of T-2 toxin in the pig cecum model. Mycotoxin Research, 2012, 28:191-198.
Wu Q, Dohnal V, Kuca K, Yuan Z. Trichothecenes: Structure-toxic activity relationships. Current Drug Metabolism, 2013,14: 641-660.
Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF kappaB. Genes & Development, 2007, 21:1396-1408.
Yao M, Dai M, Liu Z, Huang L, Chen D, Wang Y, Peng D, Wang X, Liu Z, Yuan Z. Comparison of the substrate kinetics of pig CYP3A29 with pig liver microsomes and human CYP3A4. Bioscience Reports, 2011,31(3):211-220.
Yap HY, Murphy WK, DiStefano A, Blumenschein GR, Bodey GP. Phase II study of anguidine in advanced breast cancer. Cancer Treatment Reports, 1979, 63(5):789-91.
Yiannikouris A, Jouany JP. Mycotoxins in feeds and their fate in animals:a review. Animal Research,2002,50(3):81-99.
Yoshizawa T, Swanson S P, Mirocha C J. In vitro metabolism of T-2 toxin in rats. Applied and Environmental Microbiology, 1980a, 40(5):901-906.
Yoshizawa T, Swanson S P, Mirocha C J. T-2 metabolites in the excreta of broiler chickens administered 3H-labeled T-2 toxin. Applied and Environmental Microbiology, 1980b, 38(6):1172-1177.
Yoshizawa T, Mirocha JC, Behrens JC, Swanson SP. Metabolic fate of T-2 toxin in a lactating cow. Food and Chemical Toxicology, 1981,19(1):31-39.
Yoshizawa T, Sakamoto T, Ayano Y, Mirocha CJ. 3'-hydroxy T-2 and 3'-hydroxy HT-2 toxins:new metabolites of T-2 toxin, a trichothecene mycotoxin, in animals. Agricultural and Biological Chemistry, 1982, 46(10):2613-2615.
Yoshizawa T, Takeda H, Ohi T. Structure of a novel metabolite from deoxynivalenol, a trichothecene mycotoxin, in animals. Agricultural and Biological Chemistry, 1983, 47(9):2133-2135.
Yoshizawa T, Sakamoto T, Okamoto K. In vitro formation of 3'-hydroxy T-2 and 3'-hydroxy HT-2 toxins from T-2 toxin by liver homogenates from mice and monkeys. Applied and Environmental Microbiology, 1984, 47(1):130-134.
Yoshizawa T, Sakamoto T, Kuwamura K. Structures of deepoxytrichothecene metabolites from 3'-hydroxy HT-2 toxin and T-2 tetraol in rats. Applied and Environmental Microbiology, 1985,50(3):676-679.
Yoshizawa T, Cote LM, Swanson SP, Buck WB. Confirmation of DOM-1, a de-epoxidation metabolite of deoxynivalenol, in biological fluids of lactating cows. Agricultrual and Biological Chemistry, 1986, 50:227-229.
Young JC, Zhou T, Yu H, Zhou H, Gong J. Degradation of trichothecene mycotoxins by chicken intestinal microbes. Food and Chemical Toxicology, 2007, 45(1):136-143.
Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN, Xiang J, Lin A. JNK suppresses apoptosis via phosphorylation of the proapototic Bcl-2 family protein BAD. Molecular Cell,2004,13:329-340.
Zachariasova M, Hajslova J, Kostelanska M, Poustka J, Krplov, A, Cuhr, P, Hochel I. Deoxynivalenol and its conjugates in beer:A critical assessment of data obtained by enzyme-linked immunosorbent assy and liquid chromatography coupled to tandem mass spentrometry. Analytica Chimica Acta, 2008,625:77-86.
Zamzami N, Hirsch T, Dallaporta B, Petit PX, Kroemer G. Mitochondrial implication in accidental and programmed cell death:Apoptosis and necrosis. Journal of Bioenergetics and Biomembranes, 1997, 29(20):185-193.
Zehorai E, Yao Z, Plotnikov A, Seger R. The subcellular localization of MEK and ERK—A novel nuclear translocation signal (NTS) paves a way to the nucleus. Molecular and Cellular Endocrinology, 2010, 314: 213-220.
Zhang Y, Dong C. MAPK kinases in immune response. Cellular and Molecular Immunology, 2005,2(1):20-27.
Zheng CF, Guan KL. Cytoplasmic localization of the mitogen-activated protein kinase activator MEK. Journal of Biological Chemistry, 1994, 269:19947-19952.
Zhou HR, Lau AS, Pestka JJ. Role of double-stranded RNA-activated protein kinase (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicological Sciences, 2003a, 74: 335-344.
Zhou HR, Islam Z, Pestka JJ, Rapid, Sequential Activation of Mitogen-Activated Protein Kinases and Transcription Factors Precedes Proinflammatory Cytokine mRNA Expression in Spleens of Mice Exposed to the Trichothecene Vomitoxin. Toxicological Sciences, 2003b, 72:130-142.
Zhou HR, Pestka JJ. Deoxynivalenol-induced apoptosis mediated by p38 MAPK-dependent p53 gene induction in RAW264.7 macrophages. Toxicologist, 2003,72:330.
Zhou HR, Jia Q, Pestka JJ. Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the Src family kinase Hck. Toxicological Sciences, 2005, 85:916-926.
Zinedine A, Soriano J M, Manes JCMJ. Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone:An oestrogenic mycotoxin. Food and Chemical Toxicology, 2007, 45(1):1-18.
Zollner P, Jodlbauer J, Kleinova M, Kahlbacher H, Kuhn T, Hochsteiner W, Lindner W. Concentration levels of zearalenone and its metabolites in urine, muscle tissue, and liver samples of pigs fed with mycotoxin-contaminated oats. Journal of Agriculture and Food Chemistry, 2002, 50: 2494-2501.
Accensi F, Pinton P, Callu P, Abella-Bourges N, Guelfi JF, Grosjean F, Oswald IP. Ingestion of low doses of deoxynivalenol does not affect hematological, biochemical, or immune responses of piglets. Journal of Animal Science, 2006, 84:1935-1942.
Adachi M, Fukuda M, Nishida E. Two co-existing mechanisms for nuclear import of MAP kinase:passive diffusion of a monomer and active transport of a dimer. European Molecular Biology Organization, 1999, 18:5347-5358.
Ademoyero AA, Hamilton PB. Mouth lesions in broiler chickens caused by scirpenol mycotoxins. Poultry Science, 1991,70:2082-2089.
Albarenque SM, Doi K. T-2 toxin-induced apoptosis in rat keratinocyte primary cultures. Experimental and Molecular Pathology, 2005,78:144-149.
Alexopoulos C. Association of Fusarium mycotoxicosis with failure in applying an induction of parturition program with PGF2 alpha and oxytocin in sows. Theriogenology, 2001,55:1745-1757.
Anastassiades M, Lehotay SJ, Stajnbaher D, Schenck FJ. Fast and easy multiresidue method employing acetonitrile extraction/partitioning and'dispersive solid phase extraction'for the determination of pesticide residues in produce. Int Journal of AOAC International,2003,86:412-431.
Anderson DW, Black RM, Lee CG, Pottage C, Rickard RL, Sandford MS, Webber TD, Williams NE. Structure-activity studies of trichothecenes:cytotoxicity of analogues and reaction products derivied from T-2 toxin and neosolaniol. Journal of Medicinal Chemistry, 1989, 32:555-562.
Appeldoorn MM. Vincken JP, Aura A M, Hollman PC, Gruppen H. Procyanidin dimers are metabolized by humanmicrobiota with 2-(3,4-dihydroxy-phenyl) acetic acid and 5-(3,4-dihydroxyphenyl)-y-valerolactone as the major metabolites. Journal of Agricultural and Food Chemistry, 2009, 57(3):1084-1092.
Arunachalam C, Doohan FM. Trichothecene toxicity in eukaryotes:Cellular and molecular mechanisms in plants and animals. Toxicology Letters, 2013, 217: 149-158.
Avantaggiato G, Havenaar R, Visconti A. Assessing the zearalenone binding activity of adsorbent materials during passage through a dynamic in vitro gatrointestinal model, Food Chemical Toxicology, 2003,41:1283-1290.
Awad WA, Aschenbach JR, Setyabudi FMCS, Razzazi-Fazeli E, Bohm J, Zentek J. In vitro effects of deoxynivalenol on small intestinal d-glucose uptake and absorption of deoxynivalenol across the isolated jejunal epithelium of laying hens. Poultry Science,2007,86:15-20.
Babich, H, Borenfreund, E. Cytotoxicity of T-2 toxin and its metabolites determined with the neutral red cell viability assay. Applied and Environmental Microbiology, 1991, 57(7):2101-2103.
Bae, H, Gray, JS, Li, M, Vines, L, Kim, J, Pestka, JJ. Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. Toxicological Sciences, 2010, 115: 444-452.
Balogh K, Heincinger M, Fodor J, Mezes M. Effect of long term feeding of T-2 and HT-2 toxin contaminated diet on the glutathione redox status and lipid peroxidation processes in common carp (Cyprinus carpio L.). Acta Biologica Szegediensis, 2009, 53:23-27.
Barron MG, Charron KA, Stott WT, Duvall SE. Tissue carboxylesterase activity of rainbow trout. Environmental Toxicology and Chemistry, 1999, 18:2506-2511.
Bauer J. Wertmer R, Gedek B. Zur Kontamination von Futtermitteln mit toxinbildenen Fusarienstammen und deren Toxinen. Wiener tieraztliche Monatsschrift, 1980, 67: 282-288.
Bauer J, Bollwahn W, Gareis M, Gedek B, Heinritzi K. Kinetic profiles of diacetoxyscirpenol and two of its metabolits in blod serum of pigs. Applied and Environmental Microbiology, 1985,49: 842-845.
Bauer J. The metabolism of trichothecenes in swine. Deutshce Tierarztliche Wochenschrift, 1995,102(1):50-52.
Bayliss MK, Bell JA, Jenner WN, Park GR, BWilsonoe K. Utility of hepatocytes to model species differences in the metabolism of loxtidine and to predict pharmacokinetic parameters in rat, dog and man. Xenobiotica, 1999, 29:253-268.
Beasley VR, Swanson SP, Corley RA, Buck WB, Koritz G D, Burmeister H R. Pharmacokinetics of the trichothecene mycotoxin, T-2 toxin, in swine and cattle. Toxicon, 1986,24(1):13-23.
Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proceedings of the National Academy of Sciences of the United States of America, 2001,98(24):13681-13686.
Bennett JW, Klich M. Mycotoxins. Clinical Microbiology Reviews, 2003,16(3): 497-516.
Bensassi F, Gallerne C, Sharaf El Dein O, Lemaire C, Hajlaoui MR, Bacha H. Involvement of mitochondria-mediated apoptosis in deoxynivalenol cytotoxicity. Food and Chemical Toxicology, 2012,50(5):1680-1689.
Bergmann F, Soffer D, Yagen, B. Cerebral toxicity of the trichothecene toxin T-2, of the products of its hydrolysis and of some related toxins. Toxicon, 1988,26(10): 923-930.
Bergmann F, Yagen B. Structure-activity relationships for the direct toxic action of richothecenes on rat brain. Archives of Toxicology, 1989, 63:155-156.
Berthiller F, Dall'Asta C, Schumacher R, Lemmens M, Adam G, Krska R. Masked mycotoxins:Determination of a deoxynivalenol glucoside in artificially and naturally contaminated wheat by liquid chromatography-tandem mass spectrometry. Journal of Agricultural and Food Chemistry, 2005,53:3421-3425.
Berthiller F, Sulyok M, Krska R, Schuhmacher R. Chromatographic methods for the simultaneous determination of mycotoxin conjugates in cereals. International Journal of Food Microbiology, 2007, 119:33-37.
Betina V. Structure-activity relationships among mycotoxins. Chemico-Biological Interactions,1989,71:105-146.
Beyer M, Ferse I, Humpf HU. Large-scale production of selected type A trichothecenes: the use of HT-2 toxin and T-2 triol as precursors for the synthesis of d3-T-2 and d3-HT-2 toxin. Mycotoxin Research, 2009, 25:41-52.
Biehl ML, Prelusky DB, Koritz GD, Hartin KE, Buck B, Trenholm HL. Biliary excretion and enterohepatic cycling of zearalenone in immature pigs. Toxicology and Applied Pharmacology, 1993,121(1):152-159.
Bigalke H, Rummel A. Medical aspects of toxin weapons. Toxicology, 2005,214(3): 210-220.
Bin-Umer MA, McLaughlin JE, Basu D, McCormick S, Turner NE. Trichothecene mycotoxins inhibit mitochondrial translation-Implication for the mechanism of toxicity. Toxins, 2011, 3: 1484-1501.
Bondy GS, Pestka JJ. Immunomodulation by fungal toxins. Journal of Toxicology and Environmental Health, Part B,2000,3:109-143.
Borutova R, Faix S, Placha I, Gresakova L, Cobanova K, Leng L. Effects of deoxynivalenol and zearalenone on oxidative stress and blood phagocytic activity in broilers. Archives of Animal Nutrition, 2008,62(4):303-312.
Bouaziz C, Martel C, Sharaf el dein O, Abid-Essefi S, Brenner C, Lemaire C, Bacha H. Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis. Toxicological Sciences, 2009, 110(2): 363-375.
Bouhet S, Oswald IP. The intestine as a possible target for fumonisin toxicity. Molecule Nutrition and Food Reseach, 2007, 51:925-931.
Brase S, Encinas A, Keck J, Nising CF. Chemistry and biology of mycotoxins and related fungal metabolites. Chemical Reviews, 2009, 109: 3903-3990.
Buhler DR, Rasmusson ME. The oxidation of drugs by fishes. Comparative Biochemistry and Physiology, 1968, 25:223-239.
Buhler DR, Wang-Buhler JL. Rainbow trout cytochrome P450s: purification, molecular aspects, metabolic activity, induction and role in environmental monitoring. Comparative Biochemistry and Physiology Part C, 1998, 121:107-137.
Busby WFJr, Wogan GN. Trichothecenes. In: Mycotoxins and N-Nitroso Compounds: Environmental Risks; Shank, R.C, Ed, Fla: CRC Press. Boca Raton, 1981, pp.29-41.
Busman M, Poling SM, Maragos CM. Observation of T-2 toxin and HT-2 toxin glucosides from Fusarium sporotrichioides by Liquid Chromatography Coupled to Tandem Mass Spectrometry (LC-MS/MS). Toxins, 2011,3(12):1554-1568.
Butterfield L, Storey B, Maas L, Heasley LE. c-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation. Journal of Biological Chemistry, 1997, 272:10110-10116.
Caldwell J. Conjugation reaction in foreign-compound metabolism: definition, consequences, and species variations. Drug Metabolism Reviews, 1982, 13(5): 745-777.
Campbell S, Khosravi-Far R, Rossman K, Clark G, Der C. Increasing complexity of Ras signaling. Oncogene, 1998, 17: 1395-1413.
Carlson DB, Williams DE, Spitsbergen JM, Ross RF, Bacon CW, Meredith FI, Riley RT. Fumonisin B1 promotes aflatoxin B1 and N-methyl-N'- nitrosoguanidine-initiated liver tumors in rainbow trout. Toxicology and Applied Pharmacology, 2001,172: 29-36.
Carter BC, Cannon M. Structural requirement for the inhibitory action of 12,13-epoxytrichothecenes on protein synthesis in eukaryotes. Biochemical Journal, 1977,166:399-409.
Chanh TC, Hewetson, JF. Structure/function studies of T-2 toxin mycotoxin with a monoclonal antibody. Immunopharmacology, 1991,21: 83-90.
Chatterjee K, Viscontl A, Mirocha C J. Deepoxy T-2 teraol:a metabolite of T-2 toxin found in cow urine. Journal of Agricultural and Food Chemistry, 1986, 34(4): 695-697.
Chaudhari M, Jayaraj R, Bhaskar ASB, P.V. Lakshmana Rao PV. Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells. Toxicology, 2009, 262:153-161.
Chi MS, Robison TS, Mirocha CJ. Reddy KR. Acute toxicity of 12,13-expoxytrichothecenes in one-day-old broiler chicks. Applied and Environmental Microbiology, 1978,35(4):636-640.
Chi MS, Mirocha CJ, Kurtz HJ, Weaver G, Bates F, Shimoda W, Burmeister HR. Acute toxicity of T-2 toxin in broiler chicks and laying hens. Poultry Science, 1997, 56: 103-116.
Choi SU, Choi EJ, Kim HK, Kim NY, Kwon BM, Kim SU, Bok SH, Lee SY, Lee CO. Cytotoxicity of Trichothecenes to Human Solid Tumor Cells in Vitro. Archives of Pharmacal Research,1996,19(1):6-11.
Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and-independent pathways negatively modulates its Tyrosine phosphorylation. Molecular and Cellular Biology, 1997, 17(11):6508-6516.
Cimica V, Chen HC, Iyer JK, Reich NC. Dynamics of the STAT3 Transcription Factor: Nuclear Import Dependent on Ran and Importin-b1. PLoS One, 2011,6(5):1-11.
Coddington KA, Swanson SP, Hassan AS, Buck WB. Enterohepatic circulation of T-2 toxin metabolites in the rat. Drug Metabolism Disposition, 1989, 17:600-605.
Conkova E, Laciakova A, Kovac G, Seidel H. Fusarial toxins and their role in animal diseases. Veterinary Journal,2003,165(3):214-220.
Conrady-Lorck S, Gareis M, Feng XC, Amselgruber W, Forth W, Fichtl B. Metabolism of T-2 toxin in vascularly autoperfused jejunal loops of rats. Toxicology and Applied Pharmacology, 1988,94(1):23-33.
Coppock RW, Swanson SP, Gelberg HB. Preliminary study of the pharmacokinetics and toxicopathy of deoxynivalenol (vomitoxin) in swine. American Journal of Veterinary Reseach,1985,46(1):169-174.
Corley RA, Swanson SP, Buck, WB. Glucuronide conjugates of T-2 toxin and metabolites in swine bile and urine. Journal of Agricultural and Food Chemistry, 1985,33(6): 1085-1089.
Corley RA, Swanson SP Gullo GJ, Johnson L, Beasley VR, Buck WB. Disposition of T-2 toxin, a trichothecene mycotoxin, in intravascularly dosed swine. Journal of Agricultural and Food Chemistry, 1986, 34:868-875.
Costas I. Cytochrome P450 expression in the liver of food-producing animals. Current Drug Metabolism, 2006, 7(4):335-348.
Cote LM, Dahlem AM, Yoshizawa T, Swanson SP, Buck WB. Excretion of deox ynivalenol and its metabolite in milk, urine, and feces of lactating of dairy. Journal of Dairy Science, 1986, 69(9):2416-2423.
Cote LM, Buck W, Jeffery E. Lack of hepatic microsomal metabolism of deoxynivalenol and its metabolite DOM-1. Food and Chemical Toxicology, 1987, 25:291-295.
Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signaling pathway. Seminar in Cell & Development Biology, 2008,19:414-422.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Letters,1995,364(2): 229-233.
Cundliffe E, Cannon M, Davies J. Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins. Proceedings of the National Academy of Sciences,1974,71(1):30-34.
Cundliffe E, Davies JE. Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins. Antimicrobial Agents and Chemotherapy, 1977,11(3): 491-499.
D'Mello JPF, Placinta C M, Macdonald AMC. Fusarium mycotoxins: a review of global implications for animal health, welfare and productivity. Animal Feed Sciencei Technology, 1999, 80(3-4):183-205.
Danicke S, Ueberschar KH, Halle I, Valenta H, Flachowsky G. Excretion kinetics and metabolism of zearalenone in broilers in dependence on a detoxifying agent. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2001,55(4): 299-313.
Danicke S, Ueberschar KH, Halle I, Matthes S, Valenta H, Flachowsky G. Effect of addition of a detoxifying agent to laying hen diets containing uncontaminated or Fusarium toxin-contaminated maize on performance of hens and on carryover of zearalenone. Poultry Science, 2002, 84: 1671-1680.
Danicke S, Valenta H, Klobasa F, Doll S, Ganter M, Flachowsky G. Effects of graded levels of Fusarium toxin contaminated wheat in diets for fattening pigs on growth performance, nutrient digestibility, deoxynivalenol balance and clinical serum characteristics. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2004a, 58: 1-77.
Danicke S, Valenta H, Doll S. On the toxicokinetics and the metabolism of deoxynivalenol (DON) in the pig. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2004b, 58(2):169-180.
Danicke S, Goyarts T, Valenta H, Razzazi E, Boehm J. On the effects of deoxynivalenol (DON) in pig feed on growth performance, nutrients utilization and DON metabolism. Journal of Animal Feed Science,2004c,13(4):539-556.
Danicke S, Swiech E, Buraczewska, Ueberscha KH. Kinetics and metabolism of zearalenone in young female pigs. Journal of Animal Physiology and Animal Nutrition,2005,89:268-276.
David M, Grimley PM, Finbloom DS, Larner AC. A Nuclear Tyrosine phosphatase downregulates interferon-induced gene expression. Journal of Molecular Cell Biology, 1993,13(12):7515-7521.
De Boevre M, Diana Di Mavungu J, Landschoot S, Audenaert K, Eeckhout M, Maene P, Haesaert G, De Saeger S. Natural occurrence of mycotoxins and their masked forms in food and feed products. World Mycotoxin Journal, 2012, 5(3):207-219.
Desjardins AE, McCormick SP, Appell M. Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay. Journal of Agricultural and Food Chemistry, 2007, 55:6487-6492.
Desjardins AE. From Yellow rain to green wheat:25 years of trichothecene biosynthesis research. Journal of Agricultural and Food Chemistry, 2009, 57:4478-4484.
Dohnal V, Jezkova A, Jun D, Kuca K. Metabolic pathways of T-2 toxin. Current Drug Metabolism,2008,9:77-82.
Doi K, Ishigami N, Sehata S. T-2 Toxin-induced toxicity in pregnant mice and rats. International Journal of Molecular Sciences,2008,9(11):2146-2158.
Doll S, Danicke S, Schnurrbusch U. The effect of increasing concentrations of Fusarium toxins in the diets of piglets on histological parameters of uterus. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003a, 19:73-76.
Doll S, Danicke S, Ueberschar K, Valenta H, Schnurrbusch U, Klobasa F, Flachowsky G. Effects of graded levels of Fusarium toxin contaminated maize in diets female weaned piglets. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003b, 23: 311-334.
Dol1 S, Schrickx JA, Valenta H, Danicke S, Fink-Gremmels J. Interactions of deoxynivalenol and lipopolysaccharides on cytotoxicity protein synthesis and metabolism of DON in porcine hepatocytes and Kupffer cell enriched hepatocyte cultures. Toxicological Letters, 2009, 189: 121-129.
Dombrink-Kurtzman MA, Javed T, Bennet GA, Richard JL, Cote LM, Buck WB. Lymphocyte cytotoxicity and erythrocyte abnormalities induced in broiler chicks by fumonisins B1 and B2 and moniliformin from Fusarium proliferatum Mycopathologia, 1994,124: 47-54.
Dombrink-Kurtzman MA, Dvorak TJ. Fumonisin content in masa and tortillas from Mexico. Journal of Agricultural Food Chemistry, 1999,47: 622-627.
EFSA. Scientific opinion on the risk from animal and public health related to the presence of T-2 and HT-2 toxin in food and feed. EFSA Journal, 2011,9: 2481.
Ehrlich KC, Daigle KW. Protein synthesis by mammalian cells treated with C-3-modified analogs of the 12, 13-epoxytrichothecenes T-2 and T-2 tetraol. Applied and Environmental Microbiology, 1985,50(4):914-918.
Ehrlich KC, Daigle KW. Protein synthesis inhibition by 8 oxo-12,13-epoxytrichothecenes. Biochimica et Biophysica Acta, 1987, 923:206-213.
Ember LR. Yellow rain. Chemical and Enginerring News, 1984, 9:8-34.
Engemann A, Hubner F, Rzeppa S, Humpf, HU. Intestinal metabolism of two A-type procyanidins using the pig cecum model: Detailed structure elucidation of unknown catabolites with fourier transform mass spectrometry (FTMS). Journal of Agricultural and Food Chemistry, 2012, 60(3):749-757.
English, BK, Ihle JN, Myracle A. Yi T. Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. Journal of Experimental Medicine,1993,178:1017-1020.
Eriksen GS, Pettersson H, Johnsen K, Lindberg JE. Transformation of trichothecenes in ileal digesta and faeces from pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2002, 56(4): 263-274.
Eriksen GS, Pettersson H, Lindberg J E. Absorption, metabolism and excretion of 3-acetyl DON in pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 2003,57(5):335-345.
Eriksen GS. Metabolism and Toxicity of Trichothecenes. (Ph.D dissertation). Swedish University of Agricultural Sciences:Uppsala, 2003.
Eriksen GS, Pettersson H, Lundh T. Comparative cytotoxicity of deoxynivalenol, nivalenol, their acetylated derivatives and de-epoxy metabolites. Food and Chemical Toxicology, 2004, 42:619-624.
Eriksen GS, Pettersson, H. Toxicological evaluation of trichothecenes in animal feed. Animal Feed Science and Technology, 2004, 114(1-4):205-239.
European Commission 2006. Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. Official Journal the European Union L364:5-24.
Fang H, Wu Y, Guo J, Rong J, Ma L, Zhao Z, Zuo D, Peng S. T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway. Apoptosis, 2012, 17:895-907.
Fink-Gremmels J, Malekinejad H. Clinical effects and biochemical mechanisms associated with exposure to the mycoestrogen zearalenone. Animal Feed Science and Technology, 2007, 137(3-4):326-341.
Fodor J, Meyer K, Riedlberger M, Bauer J, Horn P, Kovacs F, Kovacs M. Distribution and elimination of fumonisin analogues in weaned piglets after oral administration of Fusarium verticillioides fungal culture. Food Additives and Contaminants, 2006, 23: 492-501.
Fodor J, Meyer K, Gottschalk C, Mamet R, Kametler L, Bauer J, Horn P, Kovacs F, Kovacs M. In vitro microbial metabolism of fumonisin B-1. Food Additives and Contaminants,2007,24(4):416-420.
Fodor J, Balogh K, Weber M, Mezes M, Kametler L, Posa R, Mamet R, Bauer J, Horn P, Kovacs F, Kovacs M. Absorption, distribution and elimination of fumonisin B1 metabolites in weaned piglets. Food Additives & Contaminants Part A, 2008,25: 88-96.
Fornelli F, Minervini F, Mule G. Cytotoxicity induced by nivalenol, deoxynivalenol, and fumonisin B, in the SF-9 insect cell line. In Vitro Cellular & Developmental Biology, 2004,40(56):166-171.
Forsell J, Kateley J.R, Yoshizawa T, Pestka J. Inhibition of mitogen-induced blastogenesis in human lymphocytes by T-2 toxin and its metabolites. Applied and Environmental Microbiology, 1985,49(6):1523-1526.
Fuchs, E, Binde EMr, Heidler D, Krska R. Structural characterization of metabolites after the microbial degradation of type A trichothecenes by the bacterial strain BBSH 797. Food Additives & Contaminants,2002,19(4):379-386.
Fukuda, M, Gotoh, I, Gotoh, Y, and Nishida E. Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal. Journal of Biological Chemistry, 1996, 271:20024-20028.
Furuno T, Hirashima N, Onizawa S, Sagiya N, Nakanishi M. Nuclear shuttling of Mitogen-Activated Protein (MAP) kinase (Extracellular signal-Regulated Kinase (ERK2) was dynamically controlled by MAP/ERK Kinase after antigen stimulation in RBL-2H3 cells. Journal of Immunology, 2001,166: 4416-4421.
Galaverna G, DallAsta C, Mangia M, Dossena A, Marchelli R. Masked mycotoxins an emergingissue for food safety. Czech Journal of Food Sciences, 2009, 27:89-92.
Galhardo M, Birgel EH, Soares LMV, Furalani RPZ. Poisoning by diacetoxyscirpenol in cattle fed citrus pulp in the state of Sao Paulo, Brazil. Brazilian Journal of Veterinary Research and Animal Science,1997,34:90-91.
Garaleviciene D, Pettersson H, Elwinger K. Effects on health and blood plasma parameters of laying hens by pure nivalenol in the diet. Journal of Animal Physiology and Nimal nutrition, 2002,86(11-12):389-398.
Gardiner SA, Boddu J, Berthiller F, Hametner C, Stupar RM, Adam G, Muehlbauer GJ. Transcriptome analysis of the barley-deoxynivalenol interaction: evidence for a role of glutathione in deoxynivalenol detoxification. Molecular Plant-microbe Interactions, 2010,23(7):962-976.
Ge X, Wang J, Liu J, Jiang J, Lin H, Wu J, Ouyang M, Tang X, Zheng M, Liao M, Deng Y. The catalytic activity of cytochrome P450 3A22 is critical for the metabolism of T-2 toxin in porcine reservoirs. Catalysis Communications, 2010, 12(2): 71-75.
Gelderblom W C, Jaskiewicz K, Marasas W F, Thiel PG, Horak RM, Vleggaar R, Kriek NP. Fumonisins-novel mycotoxins with cancer promoting activity produced by Fusarium moniliforme. Applied and Environmental Microbiology, 1988, 54: 1806-1811.
Gelderblom WC, Kriek NP, Marasas WF, Thiel PG. Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1 in rats. Carcinogenesis, 1991,12: 1247-1251.
Gelderblom WC, Marasas WF, Vleggaar R, Thiel PG, Cawood ME. Fumonisins: isolation, chemical characterization and biological effects. Mycopathologia, 1992, 117:11-16.
Glavitis R, Vanyi A. More important mycotoxicosis in pigs. Magyar Allatorvosak Lapja, 1995,50: 407-420.
Glenn AE. Mycotoxigenic Fusarium species in animal feed. Animal Feed Science and Technology, 2007,137(3-4):213-240.
Glickman AH, Hamid AAR, Rickert DE, Lech AJ. Elimination and metabolism of permethrin isomers in rainbow trout. Toxicology and Applied Pharmacology, 1981, 57: 88-98.
Glickman AH, Lech JJ. Hydrolysis of permethrin, a pyrethroid insecticide, by rainbow trout and mouse tissues in vitro:a comparative study. Toxicology and Applied Pharmacology, 1981,60:186-192.
Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced Translocation of Mitogen-activated Protein Kinase to the cell surface ruffling membrane and the nucleus. Journal of Molecular Cell Biology, 1993,122(5): 1089-1101.
Gorina R, Petegnief V, Chamorro A, Planas A M. AG490 prevents cell death after exposure of rat astrocytes to hydrogen peroxide or proinflammatory cytokines: involvement of the Jak2/STAT pathway. Journal of Neurochemistry, 2005, 92: 505-518.
Groc L, Bezin, L, Jiang, H, Jackson T, Levine RA. Bax, Bcl-2 and cyclin expression and apoptosis in rat substantia nigra during development. Neuroscience letters 2001, 306(3):198-202.
Grove JF, Mortimer PH. The cytotoxicity of some transformation products of diacetoxyscirpenol. Biochemical Pharmacology, 1969,18:1473-1478.
Grove JF, Hosken M. The larvicidal activity of some 12,13-epoxytrichothece-9-enes. Biochemical Pharmacology, 1975, 24:959-962.
Guan S, He J, Young C, Zhu H, Li XZ, Ji C, Zhou T. Transformation of trichothecene mycotoxins by microorganisms from fish digesta. Aquaculture, 2009, 290:290-295.
Gutleb AC, Morrison E, Albertina JM. Cytotoxicity assays for mycotoxins produced by Fusarium strains: a review. Environmental Toxicology and Pharmacology, 2002, 11: 309-320.
He CH, Fan YH, Wang Y, Huang CY, Wang XC, Zhang HB. The individual and combined effects of deoxynivalenol and aflatoxin B1 on primary hepatocytes of cyprinus carpio. International Journal of Molecular Sciences, 2010, 11:3760-3768.
He P, Young GL, Forsberg C. Microbial transformation of Deoxynivalenol (vomitoxin). Applied and Environmental Microbiology, 1992, 58(12):3857-3863.
Hedman R, Thuvander A, Gadhasson I, Reverter M, Pettersson H. Influence of dietary nivalenol exposure on gross pathology and selected immunological parameters in young pigs. Natural Toxins, 1997a, 5(6): 238-246.
Hedman R, Pettersson H, Lindberg J E. Absorption and metabolism of nivalenol in pigs. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 1997b, 50(1):13-24.
Hedman R, Pettersson H. Transformation of nivalenol by gastrointestinal microbes. Archives of Animal Nutrition-Archiv Fur Tierernahrung, 1997, 50(4): 321-329.
Hein EM, Rose K, van't Slot G, Friedrich AW, Humpf HU. Deconjugation and degradation of flavonol glycosides by pig cecal microbiota characterized by fluorescence in situ hybridization (FISH). Journal of Agricultural and Food Chemistry, 2008, 56(6): 2281-2290.
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochemical Journal, 1998,334: 297-314.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal,2003,374:1-20.
Hendry KM, Cole EC. A review of mycotoxins in indoor air. Journal of Toxicology and Environmental Health,1993,38:183-198.
Hestbjerg H, Nielsen KF, Thrane U, Elmholt S. Production of trichothecenes and other secondary metabolites by Fusarium culmorum and Fusarium equiseti on common laboratory media and a soil organic matter agar: an ecological interpretation. Journal of Agriculture and Food Chemistry, 2002, 50:7593-7599.
Hibi M, Lin A, Smeal T, Minden A, and Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes & Development, 1993,7:2135-2148.
Hinoshita F. Nivalenol and human kidney disease? Nephron, 1997, 75:469.
Hodge DR, Hurt EM, Farrar WL:The role of IL-6 and STAT3 in inflammation and cancer. The European Journal of Cancer, 2005, 41:2502-2512.
Holstege CP, Bechtel LK, Reilly TH, Wispelwey BP, Dobmeier SG Unusual but potential agents of terrorists. Emergency Medicine Clinics of North America, 2007, 25: 549-552.
Hoyt R, Zhu W, Cerignoli F, Alonso A, Mustelin T, David M. Cutting edge: selective Tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase. Journal of Immunology, 2007, 179:3402-3406.
Huff WE, Doerr JA, Hamilton PB, Vesonder RF. Acute toxicity of vomitoxin (deoxynivalenol) in broiler chickens. Poultry Sci, 1981,60:1412-1414.
Humpf H,U, Voss KA. Effects of food processing on the chemical structure and toxicity of fumonisin mycotoxins. Molecular Nutrition & Food Research, 2004, 48:255-269.
Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends in Genetics,1995,11(2):69-74.
Inoue M, M orikawa M, Tsubio M, Sugiura M. Species difference and characterization of intestinal esterase on the hydrolyzing activity of ester-type drugs. Japanese Journal of Pharmacology, 1979, 29:9-16.
Ikawa M, Carr C, Tatsuno T. Trichothecene structure and toxicity to the green alaga Chlorella Pyrenoidosa. Toxicon, 1985,23(3):535-537.
Islam Z, Nagase M, Ota A, Ueda S, Yoshizawa T, Sakato N. Structure-function relationship of T-2 toxin and its metabolites in inducing thymic apoptosis in vivo in mice. Bioscience, Biotechnology, and Biochemistry, 1998,62(8):1492-1497.
James LJ, Smith TK. Effect of dietary alfalfa on zearalenone toxicity and metabolism in rats and swine. Journal of Animal Science,1982,55:110-118.
Jarvis BB, Eppley RM, Mazolla EP. Chemistry and bioproduction of macrocyclic trichothecenes. In: Ueno Y, ed. Trichothecenes-Chemical, Biological and Toxicological Aspects, Amsterdam:Elsevier, 1983:20-38.
Jaaro H, Rubinfeld H, Hanoch T, Seger R. Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation. Proceedings of the National Academy of Sciences of the United States of America. 1997,94, 3742-3747.
JECFA. Deoxynivalenol. Joint FAO/WHO Expert Committee on Food Additives, 56th report. Safety evaluation of certain mycotoxins in food. WHO Food Additives Series 47, Geneva, Switzerland: WHO,419-556. 2001a. Online at: www.inchem.org/documents/ jecfa/jecmono/v47je05.htm. Accessed on Aug 06, 2013.
JECFA. T-2 and HT-2. Joint FAO/WHO Expert Committee on Food Additives, 56th report. Safety evaluation of certain mycotoxins in food. WHO Food Additives Series 47, Geneva, Switzerland: WHO,419-556. 2001b. Online at: www.inchem.org/documents/jecfa/jecmono/v47je06. htm. Accessed on Aug 06, 2013.
JECFA. Zearalenone. In: Joint FAO/WHO Expert Committee on Food Additives ed. Safety evaluation of certain food additives and contaminants. WHO/FAO Food additives Series 44. IPCS-International Programme on Chemical Safety. 2000, WHO, Geneva: FAO Food and Nutrition Paper, 2006. 1-778.
Jeker N, Tamm C. Synthesis of new unnatural macrocyclic trichothecenes: 4-epiverrucarin A. Helvetica Chimica Acta, 1988, 71:1904-1913.
Jimenez M, Mateo R. Determination of mycotoxins produced by Fusarium isolates from banana fruits by capillary gas chromatography and high-performance liquid chromatography. Journal of Chromatography A, 1997, 778:363-372.
Joffe AZ. Toxicity of Fusarium poae and F. sporotrichoides and its relation to alimentary toxic aleukia. In: Purchase IFH ed., Mycotoxins. Amsterdam: Elsevier, Amsterdam, 1974.229-262.
Joffe AZ. On the question of yellow rain. In: Joffe AZ ed., Fusarium Species: Their Biology and Toxicology. Wiley, New York: 1986. 441-444.
Johnsen H, Odden E, Lie O, Johnese BA, Fonnum F. Metabolism of T-2 toxin by rat liver carboxylesterase. Biochemical Pharmacology, 1986, 35:1469-1473.
Johnsen H, Odden E, Johnsen BA, Fonnum F. Metabolism of T-2 toxin by blood cell carboxylesterases. Biochemical Pharmacology, 1988, 37(16):3193-3197.
Kaplan DH, Shankaran V, Dighe AS, Stoker E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon gdependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences, 1998, 95:7556-7561.
Karlovsky. P. Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives. Applied Microbiology and Biotechnology, 2011,91:491-504.
Katz R, Singer B. Can an attribution assessment be made for Yellow Rain? Systematic reanalysis in a chemical-and-biological-weapons use investigation. Politics and the Life Sciences,2007,26(1):24-42.
Kemppainen, BW, Riley, RT, Pace, JQ Hoerr, FJ, Joyave, J. Evaluation of monkey skin as a model for in vitro percutaneous penetration and metabolism of [3H]T-2 toxin in human skin. Fundamental and Applied Toxicology, 1986a, 7:367-375.
Kemppainen BW, Riley RT, Pace, JQ Hoerr, FJ. Effects of skin storage conditions and concentration of applied dose on [3H]T-2 toxin penetration through excised human and monkey skin. Food and Chemical Toxicology, 1986b, 24(3):221-227.
Kennedy DG, Hewitt SA, McEvoy JD, Currie JW, Cannavan A, Blanchflower WJ, Elliot CT. Zeranol is formed from Fusarium spp. toxins in cattle in vivo. Food Additives and Contaminants,1998, 15:393-400.
Kennedy NJ, Sluss HK, Jones SN, Bar-Sagi D, Flavell RA, Davis RJ. Suppression of Ras-stimiluated transformation by the JNK signal transduction pathway. Genes & Development, 2003,17:629-637.
Keppler K, Humpf HU. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorganic & Medicinal Chemistry letters, 2005,13:5195-5205.
Keppler K, Hein EM, Humpf, HU. Metabolism of quercetin and rutin by the pig caecal microflora prepared by freeze-preservation. Moloculer Nutrition and Food Research, 2006,50:686-695.
Kiessling KH, Pettersson H, Sandholm K, Olsen M. Metabolism of aflatoxin, ochratoxin, zearalenone, and three trichothecenes by intact rumen fluid, rumen protozoa, and rumen Bacteria. Applied and Environmental Microbiology, 1984, 47(5):1070-1073.
Kiessling KH. Biochemical mechanism of action of mycotoxins. Pure and Applied Chemistry, 1986, 58(2):327-338.
Kimura M, Kaneko I, Komiyama M, Takatsuki A, Koshino H, Yoneyama K, Yamaguchi I. Trichothecene 3-Oacetyltransferase protects both the producing organism and transformed yeast from related mycotoxins. Cloning and characterization of Tri101. Journal of Biological Chemistry, 1998,273:1654-1661.
King RS. Biotransformations in Drug Metabolism. In: Nassar AF, Hollenberg PF, Scatina J eds., Drug metabolism handbook: Concepts and applications. Hoboken, UAS:John Wiley & Sons; 2009.17-41.
Kleinova M, Zollner P, Kahlbacher H, Hochsteiner W, Lindner W. Metabolic profiles of the mycotoxin zearalenone and of the growth promoter zeranol in urine, liver, and muscle of heifers. Journal of Agriculture and Food Chemistry, 2002,50:769-4776.
Knupp CA, Swanson SP, Buck WB. In vitro metabolism of T-2 toxin by rat liver microsomes. Journal of Agricultural and Food Chemistry, 1986, 34:865-868.
Knupp CA, Swanson SP, Buck WB. Comparative in vitro metabolism of T-2 toxin by hepatic micrsomes prepared from phenobarbital-induced or control rats, mice, rabbits and chickens. Food and Chemical Toxicology, 1987a, 25:859-865.
Knupp CA, Corley DG, Tempessta MS, Swanson SP. Isolation and characterization of 4'-hydroxy T-2 toxin, a new metabolite of the trichothecene mycotoxin T-2. Drug Metabolism and Disposition,1987b, 15(6): 816-820.
Kobayashi J, Horikoshi T, Ryu JC, Tashiro F, Ishii K, Ueno Y. The cytochrome P-450-dependent hydroxylation of T-2 toxin in various animal species. Food and Chemical Toxicology,1987,25(7): 539-544.
Kollarczik B, Gareis M, Hanelt M. In vitro transformation of the Fusarium mycotoxins, deoxynivalenol and zearalenone, by the normal gut microflora of pigs. Journal of Natural Toxins,1994,2: 105-110.
Konigs M, Mulac D, Schwerdt G, Gekle M, Humpf HU. Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture. Toxicology, 2009, 258:106-115.
Kravchenko LV, Galash VT, Avren'eva LT, Kranauskas AE. On the sensitivity of carp, Cyprinus carpio, to mycotoxin T-2. Journal of Applied Ichthyology, 1989, 29: 156-160.
Krishnaswamy R, Devaraj SN, Padma VV. Lutein protects HT-29 cells against Deoxynivalenol-induced oxidative stress and apoptosis:prevention of NF-kappaB nuclear localization and down regulation of NF-kappaB and Cyclo-Oxygenase-2 expression. Free Radical Biology and Medicine,2010,49(1):50-60.
Kruber P, Trump S, Behrens J, Lehmann I. T-2 toxin is a cytochrome P450 1A1 inducer and leads to MAPK/p38- but not aryl hydrocarbon receptor-dependent interleukin-8 secretion in the human intestinal epithelial cell line Caco-2. Toxicology,2011,284: 34-41.
Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA. The jnkl and jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 1999, 22:667-676.
Kubena LF, Edrington, TS, Harvey, RB, Phillips TD, Sarr AB, Rottinghaus GE. Individual and combined effects of fumonisin B1 present in Fusarium moniliforme culture material and diacetoxyscirpenol or ochratoxin A in turkey poults. Poultry Science,1997,76:256-264.
Kuca K, Pohanka M. Chemical warfare agents. Mol Clin Environ Toxicol, 2010, 100: 543-58.
Kuiper-Goodman T, Scott P M, Watanabe H. Risk assessment of the mycotoxin zearalenone. Regulatory Toxicology and Pharmacology, 1987, 7: 253-306.
Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science, 1997, 278:1630-1632.
Labib S, Hummel S, Richling E, Humpf HU, Schreier P. Use of the pig caecum model to mimic the human intestinal metabolism of hispidulin and related compounds. Molecular Nutrition & Food Research,2006,50:78-86.
Lake BG, Phillips JC, Waters DG, Bayley DL, Cook MW, Thomas LV, Gilbert J, Startin JR, Baldwin NCP, Bycroft BW, Dewick PM. Studies on the metabolism of deoxynivalenol in the rat. Food and Chemical Toxicology, 1987, 25(8):589-592.
Lancova K, Hajslova J, Poustka J, Krplova A, Zachariasova M, Dostalek P, Sachambula L. Transfer of Fusarium mycotoixns and masked" deoxynivalenol (deoxynivalenol-3-glucoside) from field barely through malt to beer. Food Additives and Contaminants,2008,25:732-744.
Larsen J C, Hunt J, Perrin I, Ruckenbauer P. Workshop on trichothecenes with a focus on DON: summary report. Toxicology Letters, 2004, 153:1-22.
Laskin JD, Heck DE, Laskin DL. The ribotoxic stress response as a potencial mechanism for MAP Kinase activation in xenobiotic toxicity. Toxicological Sciences, 2002, 69: 298-291.
Lattanzio VM, Solfrizzo M, Visconti A. Enzymatic hydrolysis of T-2 toxin for the quantitative determination of total T-2 and HT-2 toxins in cereals. Analytical and Bioanalytical Chemistry, 2009,395:1325-1334.
Lattanzio VMT, Visconti A, Haidukowski M, Pascale M. Identification and characterization of new Fusarium masked mycotoxins, T2 and HT2 glycosyl derivatives, in naturally contaminated wheat and oats by liquid chromatography-high-resolution mass spectrometry. Journal of Mass Spectrometry, 2012,47:466-475.
Lavrijsen K, Houdt JV, Dyck DV, Hendrickx J, Bockx M, Hurkmans R, Meuldermans W, Jeune LL, Lauwers W, Heykants J. Comparative metabolism of flunarizine in rats, dogs and man: an in vitro study with subcellular liver fractions and isolated hepatocytes. Xenobiotica, 1992, 22:815-836.
Ledoux DR, Brown TP, Weibking TS, Rottinghaus GE. Fumonisin toxicity in broiler chicks. Journal of Veterinary Diagnostic Investigation, 1992, 4:330-333.
Lemke SL, Ottinger SE, Ake CL, Mayura K, Phillips TD. Deamination of fumonisin B1 and biological assessment of reaction product toxicity. Chemical Research in Toxicology, 2001,14:11-15.
Lenormand, P, Sardet, C, Pages, G, L'Allemain, G, Brunet A., Pouyssegur J. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. Journal of Cell Biology, 1993,122:1079-1088.
Lewis CW, Smith JE, Anderson JG, Freshney RI. Increased cytotoxicity of food-borne mycotoxins toward human cell lines in vitro via enhanced cytochrome p450 expression using the MTT bioassay. Mycopathologia, 1999, 148:97-102.
Li YC, Ledoux DR, Bermudez AJ, Fritsche KL, Rottinghaus GE. Effects of fumonisin B1 on selected immune responses in broiler chickens. Poultry Science,1999, 78: 1275-1282.
Li Y, Wang Z, Beier RC, Shen J, Smet DD, Saeger SD, Zhang S. T-2 Toxin, a trichothecene mycotoxin: review of toxicity, metabolism, and analytical methods. Journal of Agricultural and Food Chemistry, 2011,59: 3441-3453.
Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis. BioEssays, 2002, 25:17-24.
Li SN, Fan DF. Activity of esterases from different tissues of freshwater fish and responses of their isoenzymes to inhibitors. Journal of Toxicology and Environmental Health, 1997,51:149-157.
Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death. Cell,1996,87:565-576.
Liu J, Minemoto Y, Lin A. c-Jun N-Terminal Protein Kinase 1 (JNK1), but Not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Journal of Molecular Cell Biology, 2004,24(24): 10844-10856.
Liu ZY, Huang LL, Dai MH, Chen DM, Wang YL, Tao YF, Yuan ZH. Metabolism of qlaquindox in rat liver microsomes: structural elucidation of metabolites by high-performance liquid chromatography combined with ion trap/time-of-flight mass spectrometry. Rapid Comunications in Mass Sepctrometry, 2008, 22: 1009-1016.
Lun AK, Moran ETJ, Young L G, McMillan EG. Absorption and elimination of an oral dose of 3H-deoxynivalenol in colostomized and intact chickens. Bulletin Environmental Contamination and Toxicology, 1989, 42: 919-925.
Ma Y, Zhang A, Shi Z, He C, Ding J, Wang X, Mac J, Zhang H. A mitochondria-mediated apoptotic pathway induced by deoxynivalenol in human colon cancer cells. Toxicology in Vitro, 2012, 26: 414-420.
Madhyastha MS, Marquardt RR, Abramson D. Structure-activity relationships and interactions among trichothecene mycotoxins as assessed by yeast bioassay. Toxicon, 1994,32(9):1147-1152.
Mahadevan B, Marston CP, Luch A, Dashwood WM, Brooks E, Pereira C, Doehmer J, Baird WM. Competitive inhibition of carcinogen-activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar. International Journal of Cancer,2007,120:1161-1168.
Malaney S, Daly RJ. The Ras signaling pathway in mammary tumorigenesis and metastasis. Journal of Mammary Gland Biology and Neoplasia, 2001,6(1):101-113.
Malekinejad H, Maas-Bakker RF, Fink-Gremmels J. Bioactivation of zearalenone by porcine hepatic biotransformation. Veterinary Research, 2005,36(5-6):799-810.
Malekinejad H, Maas-Bakker R, Fink-Gremmels J. Species differences in the hepatic biotransformation of zearalenone. Veterinary Journal, 2006, 172:96-102.
Marasas WFO. Discovery and occurrence of the fumonisins:A historical perspective. Environ Health Perspect, 2001,109(Suppl. 2):239-243.
Marin S, Magan N, Serra J, Ramos A J, Canela R, Sanchis V. Fumonisin B1 production and growth of Fusarium moniliforme and Fusarium proliferatum on maize, wheat and barley grain. Journal of Food Science, 1999,64:921-924.
Mateo JJ, Mateo R, Jimenez M. Accumulation of type A trichothecenes in maize, wheat and rice by Fusarium sporotrichioides isolates under diverse culture conditions. International Journal of Food Microbiology, 2002, 72:115-123.
Mathur S, Constable PD, Eppley RM, Tumbleson ME, Smith GW, Tranquilli WJ, Morin D E, Haschek W M. Fumonisin B1 increases serum sphinganine concentrations but does not alter serum sphingosine concentration or induce cardiovascular changes in milk-fed calves. Toxicological Sciences, 2001,60:379-384.
McCormick SP. Fusarium head blight of wheat and barley. American Phytopathological Society, St. Paul, Minnesota, USA.2003.165-183
McKinney JD, Richard A, Waller C, Newman MC, Gerberick F. The practice of structure activity relationships (SAR) in toxicology. Toxicological Sciences, 2000, 56:8-17.
McLaughlin CS, Vaughan MH, Campbell IM, Wei CM, Stafford ME, Hansen B S. Inhibition of protein synthesis by tricho thecenes. In: Rodricks JV, Hesseltine CW, Mehlman MA eds. Mycotoxins in human and animal health. Park Forest South: Pathotox Publications,1977.261-284.
McLaughlin JE, Bin-Umer, MA, Tortora A, Mendez N, McCormick S, Turner NE. A genome-wide screen in Saccharomyces cerevisiae reveals a critical role for the mitochondria in the toxicity of a trichothecene mycotoxin. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(51): 21883-21888.
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathway:cross-talk and compensation. Trends in Biochemical Sciences, 2011,36(6):443-456.
Merrill AHJ, Sullards MC, Wang E, Voss KA, Riley RT.Sphingolipid metabolism:roles in signal transduction and disruption by fumonisins. Environmental Health Perspectives, 2001,109: 283-289.
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifinan CM. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature, 1996, 379: 645-648.
Middlebrook JL, Leatherman DL. Binding of T-2 toxin to eukaryotic cell ribosomes. Biochemical Pharmacology, 1989,38:3103-3110.
Miles CO, Erasmuson AF, Wilkins AL. Ovine metabolism of zearalenone to a-zearalanol (zeranol). Journal of Agriculture and Food Chemistry, 1996, 44:3244-3250.
Minervini F, Fornelli F, Flynn KM. Toxicity and apoptosis induced by the mycotoxinsnivalenol, deoxynivalenol and fumonisin B1 in a human erythroleukemia cell line. Toxicology in Vitro, 2004, 18:21-28.
Miranda CL, Wang JL, Henderson MC, Buhler DR. Purification and characterization of hepatic steroid hydroxylases from untreated rainbow trout. Archives of Biochemistry and Biophysics, 1989, 268(1):227-238.
Miranda CL, Wang JL, Henderson MC, Zhao X, Guengerich FP, Buhler DR. Comparison of rainbow trout and mammalian cytochrome P450 enzymes: evidence for structural similarity between trout P450 LMC5 and human P450ⅢA4. Biochemical and Biophysical Research Communications, 1991,176: 558-63.
Mirocha CJ, Pawlosky RA, Chatterjee K, Watson S, Hayes W. Analysis for Fusariun toxins in variol samples implicated in biological warfare in Southeast Asia. Journal of the Association of Official Analytical Chemists 1983,66(6): 1485-1499.
Mirocha CJ, Robison TS, Pawlosky RJ, Allen NK, Distribution and residue determination of [3H]zearalenone in broilers. Toxicology and Applied Pharmacology, 1982, 66: 77-87.
Mizuguchi R, Noto S, Yamada M, Ashizawa S, Higashi H, Hatakeyama M. Ras and signal transducer and activator of transcription (STAT) are essential and sufficient downstream components of Janus kinases in cell proliferation. Japanese Journal of Cancer Research, 2000,91(5):527-533.
Moon Y, Uzarski R, Pestka J.J. Relationship of trichothecene structure to COX-2 induction in the macrophage: selective action of type B (8-keto) trichothecenes. Journal of Toxicology and Environmental Health Part A, 2003,66:1967-1983.
Moss MO. Mycotoxin review-2. Fusarium. Mycologist, 2002,16:158-161.
Muehlbauer GJ, Boddu J, Gardiner S, Shin S, Jia H, Cho S, Mccormick S.P, Schweiger W, Lemmons M, Berthiller F, Hametner C, Kovalsky Paris PM, Torres-Acosta JA, Adam G. The role of trichothecenes in the Triticeae-Fusarium graminearum interactions. American Phytopathological Society, 2012.
Munger CE, Ivie GW, Christopher RJ, Hammock BD, Phillips TD. Acetylation/deacetylation reactions of T-2, acetyl T-2, HT-2, and acetyl HT-2 toxins in bovine rumen fluid in vitro. Journal of Agricultural and Food Chemistry, 1987, 35(5):354-358.
Nakagawa H, Ohmichi K, Sakamoto S, Sago Y, Kushiro M, Nagashima H, Yoshida M, Nakajima T. Detection of a news Fusarium masked mycotoxin in wheat grain by high-resolution LC-OrbitrapTM-MS. Food Additives and Contaminants, 2011,28(1): 1447-1456.
Nielsena KF, Thrane U. Fast methods for screening of trichothecenes in fungal cultures using gas chromatography-tandem mass spectrometry. Journal of Chromatography A, 2001,929: 75-87.
Novoa JRU, Diaz GJ. Aflatoxins and its mechanisms of toxicity in hepatic cancer. Revista Facultad de Medicina de la Universidad Nacional de Colombia, 2006, 54(2): 108-116.
Novotny WE, Dixit A. Pulmonary hemorrhage in an infant following 2 weeks of fungal exposure. Archives of Pediatrics& Adolescent medicine, 2000, 154: 271-275.
Ohta M, Ishii K, Ueno Y. Metabolism of trichothecene mycotoxins I. Journal of Cellular biochemistry, 1977, 82:1591-1598.
Ohta M, Matsumoto H, Ishii, K. Metabolism of trichothecene mycotoxins II. Journal of Biochemistry, 1978,84(3): 697-706.
Olsen M, Kiessling K H. Species differences in zearalenone-reducing activity in subcellular fractions of livers from female domestic animal species. Acta Pharmacological et Toxicolica, 1983,52:287-291.
Olsen M, Malmlof K, Pettersson H, Sandholm K, Kiessling KH. Plasma, urinary levels of zearalenone and alpha-zearalenol in a prepubertal gilt fed zearalenone. Acta Pharmacological et Toxicolica, 1985, 56:239-243.
Onji Y, Dohi Y, Aoki Y, Moriyama T, Nagami H, Uno M, Tanaka T, Yamazoe Y. Deepoxynivalenol: a new metabolite of nivalenol found in the excreta of orally administered rats. Journal of Agriculture and Food Chemistry, 1989, 37:478-481.
Parkinson A, Ogilvie BW. Biotransformation of xenbiotics. In Klaassen CD ed., Casarett and Doull's Toxicology-The Basic Science of Poisons (7th Edition):New York, USA: McGraw-Hill. 2008. 161-304.
Pace JG Metabolism and clearance of T-2 mycotoxin in perfused rat livers. Fundamental and Applied Toxicology, 1986, 7(3): 424-433.
Pawlosky RJ, Mirocha CJ. Structure of a metabolic derivative of T-2 toxin (TC-6) based on mass spectrometry. Journal of Agricultural and Food Chemistry, 1984, 32(6):1420-1423.
Pestka JJ, Tai JH, Witt MF, Dixon DE, Forsell JH. Suppression of immune response in the B6C3F1 mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone. Food Chemical and Toxicology, 1987, 25:297-304.
Pestka JJ, Yan D, King LE. Flow cytometric analysis of the effects of in vitro exposure to vomitoxin deoxynivalenol on apoptosis in murine T, B and IgA+ cells. Food and Chemical Toxicology, 1994, 32:1125-1136.
Pestka JJ. Deoxynivalenol: Toxicity, mechanisms and animal health risks. Animal Feed Science and Technology, 2007, 137: 283-298.
Pestka JJ. Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Additive and Contaminants, Part A. 2008,25(9):1128-1140.
Pestka JJ. Deoxynivalenol-induced proinflammatory gene expression: mechanisms and pathological sequelae. Toxins, 2010, 2(6):1300-1317.
Placinta CM, D'Mello JPF, Macdonald AMC. A review of worldwide contamination of cereal grains and animal feed with Fusarium mycotoxins. Animal Feed Science and Technology, 1999,78:21-37.
Poapolathep A, Sugita-Konishi Y, Doi K, Kumagai S. The fates of trichothecene mycotoxins, nivalenol and fusarenon-X, in mice. Toxicon, 2003, 41(8): 1047-1054.
Poapolathep A, Kumagai S, Suzuki H, Doi K. Development of early apoptosis and changes in T-cell subsets in mouse thymocyte primary cultures treated with nivalenol. Experimental and Molecular Pathology, 2004a, 77(2):149-152.
Poapolathep A, Sugita-Konishi Y, Phitsanu T, Doi K, Kumagai S. Placental and milk transmission of trichothecene mycotoxins, nivalenol and fusarenon-X, in mice. Toxicon,2004b,44(1):111-113.
Poapolathep A, Singhasem S, Noonpugdee C, Sugita-Konishi Y, Doi K, Kumagai S. The fate and transmission of Fusarenon-X (FX), a trichothecene mycotoxin in mice. Toxicology and Applied Pharmacology, 2004c, 197(3):367-367.
Pompa G, Montesissa C, Di Lauro FM, Fadini L. The metabolism of zearalenone in subcellular fractions from rabbit and hen hepatocytes and its estrogenic activity in rabbits. Toxicology 1986, 42(1):69-75.
Poppenberger B, Berthiller F, Lucyshyn D, Sieberer T, Schuhmacher R, Krska R, Kuchler K, Glossl J, Luschnig C, Adam G. Detoxification of the fusarium mycotoxin deoxynivalenol by a UDP-glucosyltransferase from Arabidopsis thaliana. Journal of Biological Chemistry, 2003,278(48):47905-47914.
Prelusky DB, Trenholm HL, Lawrence GA, Scott P M. Nontransmission of deoxynivalenol (vomitoxin) to milk following oral administration to dairy cows. Journal of Environmental Science and Health (B),1984, 19:593-609.
Prelusky DB, Veira DM. Trenholm HL. Plasma pharmacokinetics of the mycotoxin deoxynivalenol following oral and intravenous administration to sheep. Journal of Environmental Science and Health (B),1985,20(6):603-624.
Prelusky DB, Hamilton RM, Trenholm HL, Miller JD. Tissue distribution and excretion of radioactivity following administration of 14C-labeled deoxynivalenol to White Leghorn hens. Fundamental and Applied Toxicology, 1986a, 7(4):635-645.
Prelusky DB, Veira D M, Trenholm HL, Hartin KE. Excretion profiles of the mycotoxin deoxynivalenol, following oral and intravenous administration to sheep. Fundamental and Applied Toxicology, 1986b, 6(2):356-363.
Prelusky DB, Veira DM, Trenholm HL,Foster BC. Metabolic fate and elimination in milk, urine and bile of deoxynivalenol following administration to lactating sheep, Journal of Environmental Science and Health B,1987,22(2):125-148.
Prelusky DB, Hartin KE, Trenholm HL, Miller JD. Pharmacokinetic fate of 14C-labeled deoxynivalenol in pigs. Fundamental and Applied Toxicology, 1988,10:276-286.
Prelusky DB, Trenholm HL,Savard ME. Pharmacokinetic fate of 14C-labelled fumonisin B1 in swine. Natural Toxins, 1994, 2:73-80.
Prelusky DB, Savard ME, Trenholm HL. Pilot study on the plasma pharmacokinetics of fumonisin B1 cows following a single dose by oral gavage or intravenous administration. Natural Toxins,1995,3:389-394.
Prelusky DB, Mille JDr, Trenholm HL. Disposition of 14C-derived residues in tissues of pigs fed radiolabelled fumonisin B1. Food Additives and Contaminants, 1996a, 13: 155-162.
Prelusky DB, Trenholm HL, Rotter BA, Miller JD, Savard ME, Yeung JM, Scott PM. Biological fate of fumonisin B1 in food producing animals. Advances in Experimental Medicine and Biology, 1996b, 392:265-278.
Qing Y, Liang Y, Du Q, Fan P, Xu H, Xu Y, Shi N. Apoptosis induced by Trimethyltin chloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talk between NF-кB and MAPKs signaling pathways. Archives of Toxicology, 2013, 87(7):1273-1285.
Rafai P, Bata A, Vanyi A, Papp Z, brydl E, Jakab L, Tuboly S, Tury E. Effects of various levels of T-2 toxin on the clinical status, performance and metabolism of growing pigs. Veterinary Record, 1995a, 136: 485-489.
Rafai P, Tuboly S, Bata A, Tilly P, Vanyi A, Papp Z, Jakab L, Tury E. Effects of various levels of T-2 toxin in the immune system of growing system of growing pigs. Veterinary Record, 1995b,136:511-514.
Raisbeck MF, Rottinghaus GE, Kendall JD. Effects of naturally occurring mycotoxins on ruminants. In: Smith JE, Henderson RS eds., Mycotoxins in Animal Foods. Boca Raton: CRC Press,1991.647-677.
Regis G, Pensa S, Boselli D, Novelli F, Poli V. Ups and downs:the STAT1:STAT3 seesaw of interferon and gp130 receptor signaling. Seminars in Cell & Developmental Biology, 2008, 19: 351-359.
Remmer MDH. The role of the liver in drug metabolism. The American Journal of Medicine,1979, 49(5):617-625.
Rheeder JP, Marasas WFO, Vismer HF. Production of fumonisin analogs by Fusarium species. Applied and Environmental Microbiology, 2002, 68:2101-2105.
Riley RT, Enongene E, Voss KA, Norred WP, Meredith FI, Sharma RP, Spitsbergen J, Williams DE, Carlson DB, Merrill AHJ. Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environmental and Health Perspectives (Suppl.2), 2001,109: 301-308.
Robison TS, Mirocha CJ, Kurtz HJ, Behrens JC, Weaver GA, Chi MS. Distribution of tritium-labeled T-2 toxin in swine. Journal of Agricultural and Food Chemistry, 1979, 27:1411-1413.
Rocha O, Ansari K Doohan FM. Effects of trichothecene mycotoxins on eukaryotic cells: A review. Food Additives and Contaminants,2005,22:369-378.
Rosen RT, Rosen JD. Presence of four Fusarium mycotoxins and synthetic material in"yellow rain":Evidence for the use of chemical weapons in Laos. Biomedical Mass Spectrometry, 1982,9(10):443-450.
Rotblat B, Ehrlich M, Haklai R, Kloog Y. The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras:a potential treatment for cancer. Methods Enzymol, 2008,439:467-489.
Rotter B, Thompson BK, Clarkin S, Owen TC. Rapid colorimetric bioassay for screening of Fusarium mycotoxins. Natural Toxins, 1993,1:303-307.
Rotter BA, Prelusky DB, Pestka JJ. Toxicology of deoxynivalenol (vomitoxin). Journal of Toxicology and Environmental Health, Part A, 1996, 48:1-34.
Roybal JE, Munns RK, Morris WJ, Hurlbut JA, Shimoda W. Determination of zeranol /zearalenone and their metabolites in edible animal tissue by liquid chromatography with electrochemical detection and confirmation by gas chromatography/mass spectrometry. Journal of the Association of Official Analynical Chemists, 1988,71: 263-271.
Ryu D, Hanna MA. Eskridge KM and Bullerman LB, Heat stability of zearalenone in an aqueous buffered model system. Journal of Agriculture and Food Chemistry, 2003, 51:1746-1748.
Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF. Distinct role for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Molecular Cell Biology, 2004, 15(5):713-275.
Sakamoto T, Swanson SP, Yoshizawa T, Buck WB. Structures of new metabolites of diacetoxyscirpenol in the excreta of orally administered rats. Journal of Agricultural and Food Chemistry, 1986, 34:698-701.
Sakatsume M, Stancato LF, David M, Silvennoinen O, Saharinen P, Pierce J, Larner AC, Finbloom DS. Interferony activation of Raf-1 is Jakl-dependent and p21ras-independent. Journal of Biological Chemistry, 1998,273(5):3021-3026.
Satoh T, Hosokawa M. Carboxylesterases:structure, function and polymorphism. Biomolecules & Therapeutics,2009,17(4):335-347.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 1.Deoxynivalenol (DON),1-9.1999. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out44_en.pdf. Accessed on Aug on 06, 2013.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 4. Nivalenol. 2000-10-19. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out74_en.pdf. Accessed on Aug 06, 2013.
SCF (Scientific Committee on Food). Opinion on Fusarium toxins. Part 5. T-2 toxin and HT-2 toxin. 2001-05-30. Online at: http://europa.eu.int/comm/food/fs/sc/scf/out88_en.pdf. Accessed on Aug 06, 2013.
SCF (Scientific Committee on Food). Opinion of the Scientific Committee on Food on Fusarium toxins. Part 6: Group evaluation of T-2 toxin, HT-2 toxin, nivalenol and deoxynivalenol.2002. http://ec.europa.eu/food/fs/sc/scf/out123_en.pdf. Accessed on Aug 06, 2013.
Schoental R, Joffe AZ, Yagen B. Cardiovascular lesions and various tumors found in rats given T-2 Toxin, a trichothecene metabolite of fusarium. Cancer Reseacher, 1979, 39:2179-2189.
Schroeder JJ, Cousins R. Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocytemonolayer cultures. Proceedings of the National Academy of Sciences,1990,87:3134-3141.
Schuringa JJ, Jonk LJ, Dokter WH, Vellenga E, Kruijer W. Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components. Biochemical Journal, 2000, 1(347):89-96.
Schust J, Sperl B, Hollis A, Mayer T U, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chemistry & Biology, 2006, 13 (11):1235-1242.
Sekikawa A, Fukui H, Fujii S, Ichikawa K, Tomita S, Imura J, Chiba T, Fujimori T. REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. Carcinogenesis, 2008, 29:76-83.
Senter LH, Sanson DR, Corley DG, Tempesta MS, Rottinghaus AA, Rottinghaus GE. Cytotoxicity of trichothecene mycotoxins isolated from Fusarium sporotrichioides (MC-72083) and Fusarium sambucinum in baby hamster kidney (BHK-21) cells. Mycopathologia, 1991,13(2):127-131.
Sergent T, Parys M, Garsou S, Pussemier L, Schneider YJ, Larondelle Y. Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicology Letters, 2006, 164:167-176.
Sewald N, von Gleissenthall JL, Schuster M, Muller G, Aplin RT. Structure elucidation of a plant metabolite of 4-desoxynivalenol. Tetrahedron Asymmetry, 1992,3(7): 953-960.
Shang S, Jiang J, Deng Y. Chicken cytochrome P4501A5 is the key enzyme for metabolizing T-2 Toxin to 3'-OH-T-2. International Journal of Molecular Sciences, 2013,14(6):10809-10818.
Shanghyun S, Antonio T.A, Franz B, Wolfgang S, Gerhard A, Susan M, Gary M. Identifying and characterizing barley genes that protect against trichothecene mycotoxins. Poster. American Society of Plant Biologists, 2011.
Shank RA, Foroud NA, Hazendonk P, Eudes F, Blackwell BA. Current and future experimental strategies for structural analysis of trichothecene mycotoxins-a prospectus. Toxins, 2011,3:1518-1553.
Shephard GS, Thiel PG, Sydenham EW, Vleggaar R, Alberts JF. Determination of the mycotoxin fumonisin B1 and identification of its partially hydrolysed metabolites in the faeces of non-human primates. Food and Chemical Toxicology, 1994, 32:23-29.
Shepard GS, Thiel PG. Sydenham EW, Snijman PW, Toxicokinetics of fumonisin B2 in rats. Food and Chemical Toxicology, 1995,33:591-595.
Shi Y, Porter K, Parameswaran N, Bae HK, Pestka JJ. Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced Interleukin-6 upregulation in the macrophage. Toxicological Sciences, 2009, 109(2):247-255.
Shier WT, Shier AC, Xie W, Mirocha CJ. Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins. Toxicon, 2001,39:1435-1438.
Shifrin VI, Andreson P. Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. Journal of Biological Chemistry, 1999, 274:13985-13992.
Shima J, Takase S, Takahashi Y, Iwai Y, Fujimoto H, Yamazaki M, Ochi K. Novel detoxification of the trichothecene mycotoxin deoxynivalenol by a soil bacterium isolated by enrichment culture. Applied and Environmental Microbiology, 1997, 63: 3825-3830.
Shreeve BJ, Patterson DS, Pand Roberts BA. The carry-over of aflatoxin, ochratoxin and zearalenone from naturally contaminated feed to tissues, urine and milk of dairy cows. Food and Cosmetetic Toxicology, 1979,17:51-152.
Sintov A, Bialer M, Yagen B. Pharmacokinetics of T-2 toxin and its metabolite HT-2 toxin, after intravenous administration in dogs. Drug metabolism and disposition, 1986, 14(2):250-254.
Sintov A, Bialer M, Yagen B. Pharmacokinetics of T-2 tetraol, a urinary metabolite of the trichothecene mycotoxin, T-2 toxin in dog. Xenobiotica, 1987, 17(8): 941-950.
Smith TK. Recent advances in the understanding of Fusarium trichothecene mycotoxicoses. Journal of Animal Science, 1992, 70: 3989-3993.
Smith J, Thakur R. Occurrence and fate of fumonisins in beef. In: Jackson L ed., Fumonisins in Food. New York: Plenum Press, 1996. 39-55.
So EY, Oh J, Jang JY, Kim JH, Lee CE. Ras/Erk pathway positively regulates Jakl/STAT6 activity and IL-4 gene expression in Jurkat T cells. Molecular Immunology, 2007, 44(13):3416-3426.
Soriano JM, Dragacci S. Occurrence of fumonisins in foods. Food Research International, 2004,37: 985-1000.
Stegeman JJ. Cytochrome P450 forms in fish: catalytic, immunological and sequence similarities. Xenobiotica, 1989,19:1093-1110.
Stephanou A, Latchman DS. Opposing actions of STAT-1 and STAT-3. Growth Factors, 2005,23(3):177-182.
Sudakin, DL. Trichothecenes in the environment: relevance to human health. Toxicology Letters,2003,143:97-107.
Swanson SP, Nicoletti J, Rood HDJ, Buck WB, Cote LM. Metabolism of three trichothecene mycotoxins, T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by bovine rumen microorganisms. Journal of Chromatography-Biomedical Application, 1987a, 414: 335-342.
Swanson SP, Rood H D J, Behrens JC, Sanders AE. Preparation and Characterization of the Deepoxy Trichothecenes: Deepoxy HT-2, Deepoxy T-2 Triol, Deepoxy T-2 Tetraol, Deepoxy 15-Monoacetoxyscirpenol and Deepoxy Scirpentriol. Applied and Environment Microbiology, 1987b, 153(12): 2821-2826.
Swanson SP, Helaszek C, Buck WB, Rood HDJr, Haschek WM. The role of intestinal microflora in the metabolism of trichothecene mycotoxins. Food and Chemical Toxicology, 1988, 26(10):823-829.
Sydenham EW, Stockenstrom S, Thiel PG, Shepard GS, Koch KR, Marasas WFO. Potential of alkaline hydrolysis for the removal of fumonisins from contaminated corn. Journal of Agriculture and Food Chemistry,1995,43:1198-1201.
Sypecka Z, Kelly M, Brereton P. Deoxynivalenol and zearalenone residues in eggs of laying hens fed with a naturally contaminated diet: Effects on egg production and estimation of transmission rates from feed to eggs. Journal of Agriculture and Food Chemistry, 2004, 52(17):5463-5471.
Tang G, Minemoto Y, Dibling N, Purcell NH, Li M. Inhibition of JNK activation through NF-кB target genes. Nature, 2001,414:313-317.
Thibaut R, Schnell S, Porte C. The interference of pharmaceuticals with endogenous and xenobiotic metabolizing enzymes in carp liver: an in-vitro study. Environmental Science & Technology, 2006,40:5154-5160.
Thomas S. Refinement of the coomassie blue method of protein quantitation. A simple and linear spectrophotometric assay for less than or equal to 0.5 to 50 microgram of protein. Analytical Biochemistry, 1978,86(1):142-146.
Thompson W.L, Wannemacher RWJr. Structure-function relationships of 12,13-expoxytrichothecene mycotoxins in cell culture:comparation to whole animal lethality. Toxicon, 1986, 24(10):985-994.
Thompson WL, Wannemacher RWJr. In vivo effects of T-2 mycotoxin on synthesis of proteins and DNA in rat tissues. Toxicology and Applied Pharmacology, 1990, 105(3):482-491.
Tiemann U, Brussow KP, Kuchenmeister U, Jonas L, Pohland R, Reischauer A, Jager K, Danicke S. Changes in the spleen and liver of pregnant sows and full-term piglets after feeding diets naturally contaminated with deoxynivalenol and zearalenone. Veterinary Journal, 2008,176(2):188-196.
Trebstein A, Lauber U, Humpf HU. Analysis of Fusarium toxins via HPLC-MS/MS multimethods:Matrix effects and strategies for compensation. Mycotoxin Research, 2009,25:201-213.
Trenerry MK, Carey KA, Ward AC, Cameron-Smith D. STAT3 signaling is activated in human skeletal muscle following acute resistance exercise. Journal of Applied Physics, 2007, 102:1483-1489.
Trenholm HL, Friend DW, Hamilton RMG, Thompson BK, Hartin KE. Incedence and toxicology of deoxynivalenol as an emerging mycotoxin problem. Proc VI International Conf on the Mycoses, 1986, Pan Amercian Health Organization, Washington, DC.
Trusal LR, O'Brien JC, Ultrastructural effects of T-2 mycotoxin on rat hepatocytes in vitro. Toxicon,1986,24(5):481-488.
Trusal LR. Metabolism of T-2 mycotoxin by cultured cells. Toxicon, 1986, 24:597-603.
Tsygankov AY, Shore SK. Src: regulation, role in human carcinogenesis and pharmacological inhibitors. Current Pharmaceutical Design, 2004, 10: 1745-1756.
Tucker, JB. The "yellow rain" controversy: Lessons for arms control compliance. Nonproliferation Review, 2001,8:25-42.
Turker L, Gumus S. Quantum chemical treatment of nivalenol and its tautomers. Journal of Hazardous Materia, 2008,153:329-339.
Ueno Y, Hosoya M, Morita Y, Ueno I, Tatsuno, T. Inhibition of the protein synthesis in rabbit reticulocyte by Nivalenol, a toxic principle isolated from Fusarium nivale-growing rice. Journal of Biological Chemistry, 1968, 64(4): 479-485.
Ueno Y, Nakajima M, Sakal K, Ishii K, Sato N, Shimada N. Comparative toxicology of trichothece mycotoxins: inhibiton of protein synthesis in animal cells. Journal of Biochemistry, 1973,74: 285-296.
Ueno Y. Trichothecenes: overview address. In: Rodricks JV, Hesseltine CW, Mehlman MA eds., Mycotoxins in Human and Animal Health. Park Forest South, Illinois, USA: Phathotox Publishers. 1977. 189-207.
Ueno Y, Toxicological features of T-2 toxin and related trichothecenes. Fundamental and Applied Toxicology, 1984, 4: S124-S132.
Ueno Y. Trichothecene mycotoxins: Mycology, chemistry, and toxicology. Advances in Food & Nutrition Research,1989,3:301-353.
Usleber E, Renz V, Martbauer E, Terplan G. Studies on the application of enzyme immunoassays for the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and zearalenone. Zentralbl Veterinarmed B,1992,39:617-627.
van't Slot G, Humpf HU. Degradation and metabolism of catechin, epigallocatechin-3-gallate (EGCG), and related compounds by the intestinal microbiota in the pig cecum model. Journal of Agricultural and Food Chemistry, 2009,57:8041-8048.
van't Slot G, Mattern W, Rzeppa S, Grewe D, Humpf HU. Complex flavonoids in cocoa: synthesis and degradation by intestinal microbiota. Journal of Agricultural and Food Chemistry, 2010, 58:8879-8886.
Vanyi A, GIvatis R, Gajdacs E, Sandor G, Kovacs F. Changes in newborn piglets by the trichothecene toxin T-2. Acta Veterinaria Hungarica, 1991,39: 29-37.
Vetter IR, Arndt A, Kutay U, Gorlich D, Wittinghofer A. Structural view of the Ran-Importin beta interaction at 2.3 A resolution. Cell, 1999, 97:635-646.
Visconti A, Mirocha CJ. Identification of various T-2 Toxin metabolites in chicken excreta and tissues. Applied and Environment Microbiology, 1985, 49(5): 1246-1250.
Volotinen M, Turpeinen M, Tolonen A, Uusitalo J, Maenpaa J, Pelkonen. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metabolism and Disposition, 2007, 35(7):1135-1141.
Voss KA, Norred WP, Meredith FI, Riley RT, Saunders DS. Fumonisin concentration and ceramide synthase inhibitory activity of corn, masa, and tortilla chips. Journal of Toxicology and Environmental Health, 2006, 69:1387-1397.
Voss KA, Smith GW, Haschek WM. Fumonisins: Toxicokinetics, mechanism of action and toxicity. Animal Feed Sciencei Technology, 2007, 137(3-4):299-325.
Voyksner RD, Hagler WMJr, Swanson SS. Analysis of some metabolites of T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by thermospray high-performance liquid chromatography-mass spectrometry. Journal of Chromatography, 1987, 394: 183-199.
Vudathula DK, Prelusky DB, Ayroud M, Trenholm HL, Miller JD.Pharmacokinetic fate and pathological effects of 14C-fumonisin B1 in laying hens. Natural Toxins, 1994, 2: 81-88.
Wang E, Ross FP, Wilson TW, Riley RT, Merrill AHJ. Increases in serum sphingosine and sphinganine and decreases in complex sphingolipids in ponies given feed containing fumonisins, mycotoxins produced by Fusarium moniliforme. Journal of Nutrition,1992,122:1706-1716.
Wang J, Jiang J, Zhang H, Wang J, Cai H, Li C, Li K, Liu J, Guo X, Zou G, Wang D, Deng Y, Dai J. Integrated transcriptional and proteomic analysis with in vitro biochemical assay reveal the important role of CYP3A46 in T-2 toxin hydroxylation in porcine primary hepatocytes. Molecular & Cellular Proteomics, 2011,10(9): M111.008748.
Wang X, Liu Q, Ihsan A, Huang L, Dai M, Hao H, Cheng G, Liu Z, Wang Y, Yuan Z. JAK/STAT pathway plays a critical role in the proinflammatory gene expression and apoptosis of RAW264.7 cells induced by trichothecenes as DON and T-2 toxin. Toxicological Sciences, 2012, 127(2):412-424.
Wannenmacher RW, Wiener SL. Trichothecene Mycotoxins. In:Sidell FR, Takafuji ET, Franz DR, eds. Medical aspects of chemical and biological warfare. Washington, DC, USA:Office of the Surgeon General at TMM Publications, 1997:655-676.
Webster KA., Discher DJ, Bishopric, NH. Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. Journal of Biological Chemistry, 1993,268:16852-16858.
Wei CM, McLaughlin CS. Structure-function relationship in the 12, 13-expoxytrichothecenes-Novel inhibitors of protein synthesis. Biochemical and Biophysical Research Communications, 1974, 57(3):838-844.
Wu J, Jing L, Yuan H, Peng SQ. T-2 toxin induce apoptosis in ovarian granulosa cells of rats through reactive oxygen species-mediated mitochondrial pathway. Toxicology Letters,2011c,202:168-177.
Weidner M, Welsch T, Hiibner F, Humpf HU. Identification and apoptotic potential of T-2 Toxin metabolites in human cells. Journal of Agricultural and Food Chemistry, 2012, 60: 5676-5684.
Welsch T, Humpf HU. HT-2 Toxin 4-Glucuronide as new T-2 toxin metabolite: enzymatic synthesis, analysis, and species specific formation of T-2 and HT-2 toxin glucuronides by rat, mouse, pig, andhuman liver microsomes. Journal of Agricultural and Food Chemistry, 2012, 60: 10170-10178.
Wen Z, Zhong Z, Darnell JEJr. Maximal activation of transcription by Statl and Stat3 requires both tyrosine and serine phosphorylation. Cell, 1995, 82:241-250.
Wu Q, Dohnal V, Huang L, Kuca K, Yuan Z. Metabolic pathways of trichothecenes. Drug Metabolism. Reviews,2010,42(2):250-267.
Wu Q, Huang L, Liu Z, Yao M, Wang Y, Dai M, Yuan Z. A comparison of hepatic in vitro metabolism of T-2 toxin in rats, pigs, chickens, and carp. Xenobiotica, 2011a, 41(10):863-873.
Wu Q, Lohrey L, Cramer B, Yuan Z, Humpf HU. Impact of physicochemical parameters on decomposition of deoxynivalenol during extrusion cooking of wheat grits. Journal of Agricultural and Food Chemistry, 2011b, 59(23): 12480-12485.
Wu Q, Engemann A, Cramer B, Welsch T, Yuan Z, Humpf HU. Intestinal metabolism of T-2 toxin in the pig cecum model. Mycotoxin Research, 2012, 28:191-198.
Wu Q, Dohnal V, Kuca K, Yuan Z. Trichothecenes: Structure-toxic activity relationships. Current Drug Metabolism, 2013,14: 641-660.
Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF kappaB. Genes & Development, 2007, 21:1396-1408.
Yao M, Dai M, Liu Z, Huang L, Chen D, Wang Y, Peng D, Wang X, Liu Z, Yuan Z. Comparison of the substrate kinetics of pig CYP3A29 with pig liver microsomes and human CYP3A4. Bioscience Reports, 2011,31(3):211-220.
Yap HY, Murphy WK, DiStefano A, Blumenschein GR, Bodey GP. Phase II study of anguidine in advanced breast cancer. Cancer Treatment Reports, 1979, 63(5):789-91.
Yiannikouris A, Jouany JP. Mycotoxins in feeds and their fate in animals:a review. Animal Research,2002,50(3):81-99.
Yoshizawa T, Swanson S P, Mirocha C J. In vitro metabolism of T-2 toxin in rats. Applied and Environmental Microbiology, 1980a, 40(5):901-906.
Yoshizawa T, Swanson S P, Mirocha C J. T-2 metabolites in the excreta of broiler chickens administered 3H-labeled T-2 toxin. Applied and Environmental Microbiology, 1980b, 38(6):1172-1177.
Yoshizawa T, Mirocha JC, Behrens JC, Swanson SP. Metabolic fate of T-2 toxin in a lactating cow. Food and Chemical Toxicology, 1981,19(1):31-39.
Yoshizawa T, Sakamoto T, Ayano Y, Mirocha CJ. 3'-hydroxy T-2 and 3'-hydroxy HT-2 toxins:new metabolites of T-2 toxin, a trichothecene mycotoxin, in animals. Agricultural and Biological Chemistry, 1982, 46(10):2613-2615.
Yoshizawa T, Takeda H, Ohi T. Structure of a novel metabolite from deoxynivalenol, a trichothecene mycotoxin, in animals. Agricultural and Biological Chemistry, 1983, 47(9):2133-2135.
Yoshizawa T, Sakamoto T, Okamoto K. In vitro formation of 3'-hydroxy T-2 and 3'-hydroxy HT-2 toxins from T-2 toxin by liver homogenates from mice and monkeys. Applied and Environmental Microbiology, 1984, 47(1):130-134.
Yoshizawa T, Sakamoto T, Kuwamura K. Structures of deepoxytrichothecene metabolites from 3'-hydroxy HT-2 toxin and T-2 tetraol in rats. Applied and Environmental Microbiology, 1985,50(3):676-679.
Yoshizawa T, Cote LM, Swanson SP, Buck WB. Confirmation of DOM-1, a de-epoxidation metabolite of deoxynivalenol, in biological fluids of lactating cows. Agricultrual and Biological Chemistry, 1986, 50:227-229.
Young JC, Zhou T, Yu H, Zhou H, Gong J. Degradation of trichothecene mycotoxins by chicken intestinal microbes. Food and Chemical Toxicology, 2007, 45(1):136-143.
Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN, Xiang J, Lin A. JNK suppresses apoptosis via phosphorylation of the proapototic Bcl-2 family protein BAD. Molecular Cell,2004,13:329-340.
Zachariasova M, Hajslova J, Kostelanska M, Poustka J, Krplov, A, Cuhr, P, Hochel I. Deoxynivalenol and its conjugates in beer:A critical assessment of data obtained by enzyme-linked immunosorbent assy and liquid chromatography coupled to tandem mass spentrometry. Analytica Chimica Acta, 2008,625:77-86.
Zamzami N, Hirsch T, Dallaporta B, Petit PX, Kroemer G. Mitochondrial implication in accidental and programmed cell death:Apoptosis and necrosis. Journal of Bioenergetics and Biomembranes, 1997, 29(20):185-193.
Zehorai E, Yao Z, Plotnikov A, Seger R. The subcellular localization of MEK and ERK—A novel nuclear translocation signal (NTS) paves a way to the nucleus. Molecular and Cellular Endocrinology, 2010, 314: 213-220.
Zhang Y, Dong C. MAPK kinases in immune response. Cellular and Molecular Immunology, 2005,2(1):20-27.
Zheng CF, Guan KL. Cytoplasmic localization of the mitogen-activated protein kinase activator MEK. Journal of Biological Chemistry, 1994, 269:19947-19952.
Zhou HR, Lau AS, Pestka JJ. Role of double-stranded RNA-activated protein kinase (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicological Sciences, 2003a, 74: 335-344.
Zhou HR, Islam Z, Pestka JJ, Rapid, Sequential Activation of Mitogen-Activated Protein Kinases and Transcription Factors Precedes Proinflammatory Cytokine mRNA Expression in Spleens of Mice Exposed to the Trichothecene Vomitoxin. Toxicological Sciences, 2003b, 72:130-142.
Zhou HR, Pestka JJ. Deoxynivalenol-induced apoptosis mediated by p38 MAPK-dependent p53 gene induction in RAW264.7 macrophages. Toxicologist, 2003,72:330.
Zhou HR, Jia Q, Pestka JJ. Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the Src family kinase Hck. Toxicological Sciences, 2005, 85:916-926.
Zinedine A, Soriano J M, Manes JCMJ. Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone:An oestrogenic mycotoxin. Food and Chemical Toxicology, 2007, 45(1):1-18.
Zollner P, Jodlbauer J, Kleinova M, Kahlbacher H, Kuhn T, Hochsteiner W, Lindner W. Concentration levels of zearalenone and its metabolites in urine, muscle tissue, and liver samples of pigs fed with mycotoxin-contaminated oats. Journal of Agriculture and Food Chemistry, 2002, 50: 2494-2501.