摘要
B型单端孢霉烯族毒素是由镰刀菌产生的一组单端孢霉烯族真菌毒素,广泛污染小麦、大麦、玉米等谷物及其产品。这类毒素具有多种毒性作用,能够导致拒食、呕吐、恶心、生长迟滞、神经内分泌紊乱和免疫抑制等,严重威胁动物和人类健康。特别是拒食和呕吐,涉及严重的食源性中毒问题。然而,B型单端孢霉烯族毒素诱导拒食和呕吐反应的剂量和机理尚不清楚。B型单端孢霉烯族毒素包括5种毒素：(1)脱氧雪腐镰刀菌烯(Deoxynivalenol, DON);(2)3-乙酰基脱氧雪腐镰刀菌烯醇(3-acetyldeoxynivalenol,3-ADON);(3)15-乙酰基脱氧雪腐镰刀菌烯醇(15-acetyldeoxynivalenol,15-ADON);(4)镰刀菌酮-X(Fusarenon X, FX);(5)雪腐镰刀菌烯醇(Nivalenol, NIV)。本研究以这5种毒素为研究对象,建立了小鼠急性拒食模型；以DON为代表毒素,从迷走神经和促炎性细胞因子等方面着手,探索了DON诱导拒食反应的机理；比较研究了B型单端孢霉烯族毒素诱导拒食反应的量效关系和持续时问,制定了B型单端孢霉烯族毒素诱导拒食反应的最大无作用剂量(No observed adverse effect, NOAEL)和最小有作用剂量(Lowest observed adverse effect, LOAEL);建立了水貂急性呕吐模型,比较研究了B型单端孢霉烯族毒素诱导呕吐反应的量效关系,呕吐发生率,潜伏期和持续时间,制定了B型单端孢霉烯族毒素诱导呕吐反应的NOAEL和LOAEL,以及半数致呕吐量(50%emetic dose, ED50);并以DON为代表毒素,从神经递质5-羟色胺(Serotonin,5-HT),神经肽肽YY(Peptide YY, PYY)和胆囊收缩素(Cholecystokinin, CCK)的调控作用着手,探索了DON诱导呕吐反应的机理。
试验Ⅰ小鼠急性拒食模型的建立及DON诱导小鼠拒食反应的机理研究
应用B6C3F1雌性小鼠建立了一种急性拒食模型,分别通过腹腔注射和灌胃攻毒DON(剂量范围0-5mg-kg-1),然后测定小鼠攻毒后16h内的采食量,研究了DON诱导拒食反应的量效关系,持续时间和耐受性。应用迷走神经切断术,研究了迷走神经在DON诱导的拒食反应中所起的作用。采用DON诱导拒食反应的NOAEL(2.5mg·kg-1)对小鼠进行灌胃攻毒,对照组灌胃PBS,并在攻毒0,2和6h后取小鼠脾脏,应用实时荧光定量PCR(Real-time PCR)技术检测DON对细胞因子白细胞介素IL-1p和IL-6的mRNA基因表达的影响。结果表明：DON能够诱导急性拒食反应,腹腔注射或灌胃攻毒后2h就会发生明显的拒食反应,并且具有剂量依赖性。腹腔注射攻毒时,DON诱导拒食反应的NOAEL和LOAEL分别为0.5和1mg-kg-1,而灌胃攻毒时分别为1和2.5mg-kg-1. DON诱导的拒食反应是短暂的,当给予1mg-kg-1DON时,拒食反应持续3h；而给予5mg-kg-1DON时,拒食反应持续6h。攻毒后2-16h, DON又能够诱导促进食欲反应,并且也呈剂量依赖性。48h重复进行DON攻毒会对其诱导的拒食反应产生轻微的耐受作用。但是7d重复进行DON攻毒却不会产生耐受,说明这种轻微的耐受作用是可逆转的。而切断迷走神经对DON诱导的拒食反应无显著影响,说明DON诱导的拒食反应不涉及迷走神经通路。DON能够上调脾脏中IL-1p和IL-6mRNA表达,灌胃攻毒后2h, IL-1p和IL-6的表达达到峰值；而攻毒6h后,IL-1β和IL-6mRNA的表达回到基础水平,说明DON诱导的急性拒食反应与脾脏中IL-1p和IL-6mRNA的表达呈正相关。
试验ⅡB型单端孢霉烯族毒素诱导小鼠拒食反应的比较研究
应用上一章建立的小鼠急性拒食模型,分别通过腹腔注射和灌胃攻毒(剂量范围0-5mg-kg-1),然后测定小鼠攻毒后16h内的采食量,研究了B型单端孢霉烯族毒素中的3-ADON、15-ADON、FX和NIV诱导的拒食反应,并与DON诱导的拒食反应进行了比较。结果表明：与DON相似,腹腔注射和灌胃攻毒3-ADON和15-ADON诱导的拒食反应是急性的,短暂的,攻毒后2h就会发生明显的拒食反应,并且具有剂量依赖性,但是仅仅持续数小时,攻毒后16h,食欲恢复正常。腹腔注射攻毒时,3-ADON和15-ADON诱导拒食反应的NOAEL和LOAEL分别为0.5和1mg-kg-1,而灌胃攻毒时分别为1和2.5mg-kg-1.与之不同的是,腹腔注射或灌胃攻毒FX和NIV能够诱导急性的,持续性的拒食反应,反应能够持续48-96h。FX腹腔注射和灌胃攻毒的NOAEL都是0.025mg-kg-1,而LOAEL都是0.25mg-kg-1bw。而NIV在腹腔注射攻毒时的NOAEL和LOAEL分别为0.01和0.1mg-kg"1,灌胃攻毒时分别为0.1和1mg-kg"1.以上结果说明,腹腔注射攻毒B型单端孢霉烯族毒素诱导的拒食反应强于灌胃。根据NOAEL和LOAEL,B型单端孢霉烯族毒素诱导拒食反应的毒性顺序为：NIV> FX> DON≈3-ADON≈15-ADON(腹腔注射)；FX>NIV>DON≈3-ADON≈15-ADON：灌胃)。
试验Ⅲ水貂急性呕吐模型的建立及B型单端孢霉烯族毒素诱导水貂呕吐反应的比较研究
建立了一种水貂急性呕吐模型,分别通过腹腔注射和灌胃攻毒(剂量范围0-1mg-kg-1),监测了B型单端孢霉烯族毒素DON、15-ADON、3-ADON、FX和NIV诱导呕吐反应的潜伏期、持续时间、发生率和反应强度,比较了5种毒素诱导呕吐反应的能力。并应用SAS等统计学方法分析得到了B型单端孢霉烯族毒素诱导呕吐反应的NOAEL、LOAEL和EDso。结果表明：B型单端孢霉烯族毒素能够诱导急性短暂的呕吐反应,攻毒后几十分钟就会发生反应,持续数小时,并具有剂量依赖性。随着剂量的增加,呕吐反应的潜伏期会缩短,持续时间会延长,发生率和反应强度会增高。腹腔注射攻毒,DON, FX和NIV的NOAEL和LOAEL分别为0.05和0.1mg-kg-1,而15-ADON和3-ADON的NOAEL都是0.1mg-kg-1, LOAEL分别为0.25和0.2mg-kg-1.灌胃攻毒,DON和FX的NOAEL和LOAEL分别是0.01和0.05mg-kg-1,15-ADON的NOAEL和LOAEL分别是0.01和0.1mg-kg-1,3-ADON的NOAEL和LOAEL分别是0.05和0.25mg-kg-1, NIV的NOAEL和LOAEL分别是0.1和0.25mg-kg-1.腹腔注射攻毒,DON、15-ADON、3-ADON. FX和NIV的EDso分别为80,170,180,70, and60μg·kg-1;而灌胃攻毒DON、15-ADON、3-ADON、FX和NIV的ED5o分别为30,40,290,30and250μg-kg-1.参照NOAEL、LOAEL和EDso,B型单端孢霉烯族毒素诱导呕吐反应的毒性顺序为：NIV≈FX≈DON>15-ADON≈3-ADON(腹腔注射)；DON≈FX≈15-ADON> NIV>3-ADON((灌胃)。
试验ⅣDON诱导水貂呕吐反应的机理研究
应用上一章建立的水貂急性呕吐模型,研究5-HT3受体拮抗剂格拉司琼(Granisetron, GRA)、Y2受体拮抗剂JNJ-31020028和CCK1受体拮抗剂地伐西匹(Devezepide, DEV)对DON诱导呕吐反应的阻断作用,探索DON诱导呕吐反应的通路。然后,分别采用DON诱导呕吐反应的LOAEL和100%致呕吐剂量0.1和0.25mg-kg-1对水貂进行腹腔注射攻毒,对照组腹腔注射PBS,分别在攻毒后15,30,60和120min采血,应用直接竞争ELISA法测定外周血中DON的含量、神经递质5-HT、神经肽PYY和CCK的表达；同时监测水貂在0-120min内的呕吐反应。结果表明：在呕吐拮抗剂试验中,CCK1受体拮抗剂DEV对DON诱导的呕吐反应无明显阻断作用；Y2受体拮抗剂，fNJ-31020028能够显著减弱DON诱导的呕吐反应；而5-HT3受体拮抗剂GRA既能够彻底阻断DON诱导的呕吐反应,也能够部分阻断PYY诱导的呕吐反应。外周血中DON的浓度在15-30min达到峰值,然后迅速下降,在120min时回到基础水平；DON能够上调外周血中5-HT和PYY的表达,并且具有剂量依赖性。DON腹腔注射攻毒后60min,外周血中5-HT和PYY的浓度达到峰值,而攻毒后120min,外周血中5-HT和PYY的浓度回到基础水平。外周血中PYY的浓度在30min时开始升高,而5-HT在30min时没有明显变化,在60min时才开始升高,说明PYY可能能够诱导5-HT的分泌。而DON对外周血中CCK的表达无明显作用。通过监测水貂在0-120min内的呕吐反应发现,大部分的呕吐反应发生在0-60min,120min之后无呕吐反应发生,说明呕吐反应与血浆中5-HT和PYY的浓度呈正相关。本研究说明,DON诱导的呕吐反应可能是由5-HT和PYY介导的,而PYY诱导的呕吐反应部分涉及5-HT通路。
The8-ketotrichothecenes, sometimes referred to as Type B trichothecenes, are a group of toxic sesquiterpenoid mycotoxins produced by Fusarium, fungus that frequently contaminates cereal staples such as wheat, barley and corn. These mycotoxins have been associated with a spectrum of toxic effects in experimental animals that include anorexia, emesis, nausea, growth retardation, neuroendocrine changes and immunosuppression, especially anorexia and emesis which involve food poisoning.These toxins have been recognized as a severe public health threat for animals and human beings.8-ketotrichothecenes include five toxins:(1) deoxynivalenol (DON),(2)3-acetyldeoxynivalenol (3-ADON),(3)15-acetyldeoxynivalenol (15-ADON),(4) fusarenon X (FX) and (5) nivalenol (NIV). Our lab developed an acute mouse bioassay model for conducting8-ketotrichothecenes-induced anorexia study. We pursued the mechanisms of DON-induced anorexia through vagus nerve and cytokines; We compared the potencies of8-ketotrichothecenes in the mouse anorexia model following intraperitoneal (ip) and oral administration and determined the dose response, duration, no observed adverse effect (NOAEL) and lowest observed adverse effect (LOAEL) of anorexia. Then, our lab developed an acute mink emesis model for conducting8-ketotrichothecenes-induced emesis study. We compared potencies of8-ketotrichothecenes in emetic effects following ip and oral administration and determined the latency, duration, incidence and intensity of emesis.We also established the NOAEL, LOAEL and50%emetic dose (ED5o) of8-ketotrichothecenes-induced emesis; The mechanisms of DON-induced emesis were elucidated through regulation of neurotransmitter serotonin (5-HT), neuropeptide peptide YY(PYY) and Cholecystokinin (CCK).
1. Characterization and mechanisms of DON-induced anorexia using mouse bioassay
A short-term mouse model was devised to investigate induction of food refusal by the common foodborne trichothecene DON. Mice were dosed DON by either ip or oral exposure at0-5mg-kg-1and food intake were measured in16h post-dosing. Dose response, duration and tolerance of DON-induced anorexia were determined. In order to determine the role of vagus nerve in DON-induced anorexia, we conducted anorexia study using vagotomy mouse. In order to determine the role of cytokines in DON-induced anorexia, we determined the mRNA expressions of interleukin-1β (IL-1β) and interleukin-6(IL-6) in mouse spleen using Real-time PCR at0,2and6h after oral exposure to2.5mg·kg-1DON. The results presented herein indicated that DON dose-dependently induced anorexia within2h of exposure when administered either by ip injection or by oral gavage. The no observed adverse effect and lowest observed adverse effect levels in this assay were0.5and1mg-kg-1for ip exposure and1and2.5mg-kg-1for oral exposure, respectively. DON's effects on food intake were transient, lasting up to3h at1mg-kg-1and up to6h at5mg-kg"1. Interestingly, a dose-dependent orexigenic response was observed in the14h following the initial2h food intake measurement. Toxin-treated mice exhibited partial resistance to feed refusal when exposed to DON subsequently after2d, but not after7d suggesting that this modest tolerance was reversible. DON-induced feed refusal were not affected after vagotomy suggesting that vagus nerve was not associated with DON induced feed refusal. The mRNA expressions of IL-1β and IL-6were upregulated by DON in mouse spleen and reached peak levels at2h post-dosing, and back to basal levels at6h post-dosing, suggesting that DON-induced anorexia was correlated with mRNA expressions of IL-1β and IL-6in mouse spleen.
2. Comparison of murine anorectic responses to the8-ketotrichothecenes
The anorectic effects of structurally related8-ketotrichothecenes,3-acetyldeoxynivalenol (3-ADON),15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX) and nivalenol (NIV) were determined in the mouse model for anorexia induction from last chapter and compared with DON. As previously observed for DON, anorectic responses to3-ADON and15-ADON in the B6C3F1female mouse following both intraperitoneal (ip) and oral exposure were transient, lasting only a few hours, with food intake recovering to control levels within16h. For both ADONs, the no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL) were0.5and1mg-kg-1following ip exposure, respectively, and1and2.5mg-kg-1after oral exposure, respectively. In contrast, food refusal persisted from48h to96h following ip and oral exposure to FX and NIV. For both ip and oral FX exposure, the NOAEL was0.025mg-kg-1and LOAEL was0.25mgkg-1, whereas the NOAELs and LOAELs for NIV were0.01and0.1mg·kg-1, respectively, after ip exposure and0.1and1mg-kg-1, respectively following oral exposure. Both these data and a prior DON study suggest that anorectic responses to8-ketotrichothecenes were always greater when administered ip as compared to oral exposure and follow an approximate rank order of NIV>FX>DON≈3-ADON≈15-ADON for ip exposure and FX>NIV>DON≈3-ADON≈15-ADON for oral exposure.
3. Characterization and comparison of emetic responses to the8-ketotrichothecenes using mink bioassay
A short-term mink model was devised to investigate induction of emesis by the8-ketotrichothecenes. The emetic capacities of the DON,15-ADON,3-ADON, FX and NIV were compared in female mink via ip and oral administration. In this model, the incidence, latency, duration, and intensity of emesis of all compounds were compared. The NOAELs, LOAELs and ED50of emesis were analyzed by SAS and other statistics methods. The results presented herein indicated that all five congeners dose-dependently induced rapid and short term emesis by both administration methods. Emesis was observed in1hour and lasted several hours. With increasing doses, there were marked decreases in latency to emesis with corresponding increases in emesis duration and number of emetic events. Following IP exposure, the NOAELs and LOAELs were0.05and0.1mg·kg-1, respectively, for DON, FX and NIV. For15-ADON and3-ADON, the NOAELs were both0.1mg-kg-1and LOAELs were0.25and0.2mg-kg-1, respectively. Following oral exposure, the NOAELs and LOAELs were0.01and0.05mg-kg-1for both DON and FX. The NOAEL and LOAEL for15-ADON were0.01and0.1mg-kg-1, for3-ADON,0.05and0.25mg-kg-1, and for NIV,0.1and0.25mg-kg-1, respectively. The effective doses resulting in emetic events in50% of the animals (ED50) for ip exposure to DON,15-ADON,3-ADON, FX and NIV were80,170,180,70, and60μg-kg-1respectively, and for oral exposure were30,40,290,30and250μg-kg-1, respectively. Emetic responses to8-ketotrichothecenes follow an approximate rank order of NIV≈FX≈DON>15-ADON≈3-ADON for ip exposure and DON≈FX≈15-ADON>NIV>3-ADON for oral exposure based on NOAELs, LOAELs and ED50.
4. Mechanisms of DON-induced emesis using mink bioassay
The mechanisms of DON-induced emesis were explored in mink model from last chapter.5-HT3receptor antagonist granisetron, Y2receptor antagonist JNJ-31020028and CCK1receptor antagonist devezepide were used to block DON-induced emesis. Then, mink were dosed DON at0.1and0.25mg-kg'1via ip exposure and collected blood at15,30,60and120min post-dosing. DON concentration, neurotransmitter5-HT, neuropeptide PYY and CCK in plasma were measured by ELISA kits. Emetic events were monitored during0-120min. The results presented herein indicated that CCK1receptor antagonist devezepide had no obvious effects on DON-induced emesis. While, Y2receptor antagonist JNJ-31020028significantly attenuated DON-induced emesis. However, that5-HT3receptor antagonist granisetron could totally block DON-induced emesis, partially block PYY induced emesis. Plasma DON concentration reached the peak level in15-30min, declined very quickly thereafter and back to basal level at120min. DON dose-dependently upregulated plasma5-HT and PYY. Plasma5-HT and PYY reached the peak level at60min post-dosing and back to basal level at120min. Plasma PYY increased at30min post-dosing, while5-HT had no changes at that time and increased at60min, suggesting that PYY might induce the release of5-HT. Furthermore, plasma CCK had no changes post-dosing. Most of emetic events happened during0-60min and no emetic events were observed after120min, suggesting that DON-induced emesis might correlate with plasma5-HT and PYY. These results indicated that DON-induced emesis might mediate via5-HT and PYY, while PYY-induced emesis might mediate by5-HT.
引文
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