内分泌干扰物TCDD与PCBs联合暴露复合效应代谢组学研究
|
摘要
内分泌干扰物(endocrine disruptors,EDs)是我国广泛存在、危害效应十分严重的环境与食品污染物。目前,EDs已成为全世界广泛关注的安全卫生问题之一,特别是其联合暴露的复合效应更是令人担忧。2,3,7,8-四氯二苯并对二噁英(2,3,7,8-tetrachlorodibenzo-p-dioxin,TCDD)和多氯联苯类(polychlorinated biphenyls,PCBs)化合物是典型的EDs,由于它们广泛分布并共存于环境中,具有可生物蓄积、难以降解、远距离迁移及高毒等特性,已成为环境毒理学研究的热点。但有关EDs的危险性认识及相关毒理学研究主要关注单一污染物的效应,且研究手段仍主要沿用传统的毒性评价方法,而对于它们联合暴露的复合效应还没有进行系统研究。基于我国多种EDs共存污染的现状,应用新技术开展对多种环境与食品污染物复合毒性效应研究具有十分重要的理论和现实意义。基于核磁共振(nuclear magnetic resonance,NMR)的代谢组学技术是近年来发展起来的新技术,已广泛地应用于毒理学研究。因此,本研究拟将代谢组学技术与传统毒性评价技术相结合,对我国环境污染中危害较严重的内分泌干扰物TCDD与PCBs联合暴露的复合毒性效应进行系统研究,探讨复合效应作用模式及作用机制,寻找复合效应的候选生物标志物,并探讨代谢组学技术在EDs复合效应研究中的应用前景。
首先,建立针对EDs毒性研究的代谢组学技术平台。采用2×2析因设计将20只SD大鼠随机分为4组,即对照组、PCBs单独染毒组(Aroclor1254 10 mg/kg)、TCDD单独染毒组(TCDD 10μg/kg)和联合染毒组(TCDD 10μg/kg+Aroclor1254 10 mg/kg),每组5只。灌胃染毒,每天1次,连续3 d。用代谢笼收集各组大鼠染毒前、染毒过程中每天24 h的尿液,对其进行核磁共振氢谱(~1H NMR)分析,建立特征代谢谱,采用主成分分析法(principal component analysis,PCA)对结果进行统计分析。各组间进行的PCA分析结果显示,各样本基本集中分布于得分图的椭圆形(95%置信区内)的4个区域,各染毒组大鼠尿液代谢组轨迹能够明显地与对照组分开,单独与联合染毒组大鼠尿液代谢组轨迹也能明显分开,提示各组大鼠尿液的代谢组都发生了明显的改变。本研究表明,采用代谢组学方法能够很好地表征和描述TCDD与PCBs联合暴露导致的代谢变化,并能对其复合毒性效应进行说明,表明已成功地建立了基于~1H NMR的代谢组学技术平台。代谢组学方法的灵敏性优于传统毒性评价方法,该技术用于EDs复合效应研究具有良好的应用前景。
在此基础上,本研究利用所建立的代谢组学技术平台,结合传统毒性评价方法对TCDD与PCBs联合暴露复合毒性效应进行了研究,观察联合暴露后大鼠尿液的代谢模式的变化及其与血液生化指标和组织病理学的相关性,寻找复合效应的候选生物标志物,探讨TCDD与PCBs联合暴露毒性效应机制。SD大鼠每天灌胃染毒1次,连续6 d。用代谢笼收集各组大鼠尿液,测定~1H NMR谱,并进行血清生化指标、组织病理学和组织氧化损伤检测。结果表明,各染毒组大鼠均呈现不同程度的毒性效应,表现为:体重下降、脏器系数与血清生化指标改变、组织病理学改变以及组织发生氧化损伤,这些毒性效应在联合染毒组表现更为明显。运用~1H NMR代谢组学技术研究TCDD与PCBs联合暴露对大鼠尿液代谢产物谱影响的结果表明:各组在不同染毒条件下的代谢模式可明显区分开,自染毒第一天起,各染毒组大鼠的代谢组就明显偏离对照组和染毒前的代谢组成分,且各染毒组的代谢组轨迹不同,提示其毒性作用机制可能不同。大鼠尿液~1H NMR谱改变及其相对位置与其毒性呈较强的对应关系。通过对两种评价方法结果的对比,可发现不同染毒代谢组的改变以及毒性发生发展过程中代谢组的改变均与常规毒性检测指标相符。尿样~1H NMR谱PCA分析结果表明,大鼠尿液中2-酮戊二酸、柠檬酸、琥珀酸、肌酸、乳酸、N-氧三甲胺(trimethylamine-N-oxide,TMAO)、马尿酸、2-羟异戊酸、牛磺酸、二甲胺(dimethylamine,DMA)、肌酐、葡萄糖等代谢产物水平在染毒后发生了改变,且联合暴露组的改变更明显。这些改变了的代谢成分可能成为研究复合毒性效应候选生物标志物。另外,提示联合暴露的毒性效应可能与线粒体功能受损、三羧酸循环的能量代谢异常以及葡萄糖、脂肪和氨基酸代谢紊乱有关。
进而对TCDD和PCBs联合暴露复合效应的作用模式及作用机制进行研究。SD大鼠每天灌胃染毒1次,连续12 d。染毒结束后处死大鼠,取血清测定血液生化指标,取组织进行组织病理学检查,同时检测组织脂质过氧化和组织中细胞色素P450 1A1(cytochromeP450 1A1,CYP1A1)、热休克蛋白70(heat shock protein 70,HSP70)的表达情况。结果表明,TCDD与PCBs单独及联合染毒均引起明显的毒性效应,表现为:动物体重明显下降、脏器系数与血清生化指标改变、组织病理学改变以及组织发生氧化损伤、诱导组织CYP1A1和HSP70蛋白高表达,且这些毒性效应在联合染毒组表现更为明显。通过芳烃受体诱导组织CYP1A1高表达,导致氧化损伤在TCDD和PCBs复合毒性效应中可能发挥重要的作用。此外,组织中丙二醛(malondialdehyde,MDA)、超氧化物歧化酶(superoxidedismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxide,GSH-Px)、CYP1A1和HSP70蛋白可能成为TCDD与PCBs复合毒性效应的候选分子生物标志物。析因方差分析结果表明,TCDD与PCBs的复合效应很复杂,在本实验条件下,对于不同的毒性评价终点联合作用模式表现不一,既有相加作用,又有协同和拮抗作用。
综合本研究结果,在本实验条件下,可以得到如下结论:①利用代谢组学技术可以区分不同毒性作用机制的代谢表型,代谢组学技术用于EDs复合效应研究具有良好的应用前景。②代谢组学分析结果与常规检测指标具有良好的相关性且具更多优势。③TCDD与PCBs单独及联合暴露均可引起大鼠毒性效应,联合暴露的复合毒性效应更显著。④TCDD与PCBs复合效应的作用模式复杂,主要表现为相加或协同作用。⑤利用代谢组学技术结合传统毒性评价方法筛选出了一些复合效应候选生物标志物。⑥通过芳烃受体诱导组织CYP1A1高表达,导致氧化损伤在TCDD和PCBs复合毒性效应中可能发挥重要的作用。另外,复合毒性效应可能还与线粒体功能受损、三羧酸循环中能量代谢异常以及葡萄糖、脂肪和氨基酸的代谢紊乱有关。
Endocrine disruptors(EDs) are widely dispersed environmental and food contaminants in our country that poses a great risk to the public health.They have been one of the widespread current subjects for concern in health safety throughout the world,especially their combined effects of combined exposure.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) and polychlorinated biphenyls(PCBs) are typical EDs.At present,they are one of the hot spots in the field of environmental toxicology because of their extensive disposition and coexistence in the environment,persistence,bioaccumulation,migration and high toxicity.But most researches on the toxicity and human health hazards of these EDs have focused primarily on toxicology studies conducted on individual compound,and traditional toxicity evaluating techniques remain mainstream,but the possible interactions of combined exposure to EDs have not been investigated systematically.However,considering the facts that humans are ubiquitously simultaneously exposed daily to complex mixtures of environmental contaminants in our country, assessment of the mixture effects of multiple pollutants with the new technique is of more theoretical and actual significance.Nuclear magnetic resonance(NMR)-based metabonomic approach is a newly developed technology that has been extensively applied in the studies of toxicology.Therefore,the present study was designed to assess the potential combined toxic effects of combined exposure to TCDD and PCBs with metabonomics combined with conventional toxicologic technologies,so as to explore the possible modes and mechanisms of combined effects and select the possible biomarkers of combined toxicity.The potential application of metabonomics in the combined effects study of EDs was explored.
First,the platform,based on metabonomics technique,for EDs toxicity study was established.Twenty Sprague-Dawley rats were subjected to 2×2 factorial experimental design and assigned randomly into four groups of five rats each group,including the control group,the PCBs exposure group,the TCDD exposure group,and the combined-exposure group.Rats were intragastrically administered vehicle(olive oil),PCBs(Aroclor1254,10 mg/kg),TCDD(10μg/kg),or the combination(10μg/kg TCDD+10 mg/kg Aroclor1254),once a day for consecutive 3 days.Rats were housed in metabolism cages and the 24 hour urinary samples of each rat were collected before and after exposure and its hydrogen nuclear magnetic resonance (~1H NMR) spectra were measured,spectral characteristics for each group were summarized and the data were analyzed by principal component analysis(PCA).Based on the results from PCA in all groups,the samples were primarily distributed in four regions of the scoring oval(95% confidence intervals).The urine metabonomic trajectory of all exposure groups animals could obviously separated with that of control animals,and there were separated between the exposure to TCDD or PCBs group and the combined-exposure group,which suggested that all groups had a distinct metabonomic spectra.The results of this partial study suggest that metabonomic techniques can be used to characterize the metabolic consequence combined exposure to TCDD and PCBs,to elucidate the combined toxic effects and mechanism,that the platform based on metabonomics technique has been successfully established.Metabonomics technology can be proved more sensitive than traditional method for toxicity evaluation.Metabonomics is a promising new technology for the combined effects study of EDs.
Secondly,using the metabonomics technique combined with conventional toxicologic technologies to investigate the potential combined toxic effects of combined exposure to TCDD and PCBs,to observe the relationship of the metabonomic pattern of rat urine with blood biochemical indices and histopathology and select the possible biomarker candidates of combined toxicity,to explore the toxic effect mechanism of combined exposure.SD rats were intragastrically administered TCDD,PCBs,or the combination daily for consecutive 6 days.The 24 hour urinary samples of each rat were collected before and after exposure and its nuclear magnetic resonance spectra were measured,the serum biochemical analysis,histopathology examination and tissue oxidative damage detection were taken.The results showed that all treatment groups produced different degree toxicities,as characterized by losses in body weight, changes in organ coefficients and serum biochemistry parameters,histological changes and tissue oxidative damage.Most of these effects were more remarkable in the combined-exposure group.The ~1H NMR spectroscopic and pattern recognition methods were used to detect alteration of the urine metabolite expression profile of combined exposure to TCDD and PCBs. Results showed that all treatment groups could be readily distinguished in the PCA analysis diagram without overlap,and just after exposure,the urine metabonomics trajectory biased from that of the controls or pre-exposure.It was well in agreement with the toxic injury differentia of differently treated rats that the metabonomic spectra of urine from these rats could also be distinguished easily from each other.The result of rat urine metabonomic pattern change was in accordance with that of traditional toxicity evaluation.The PCA analysis of urine ~1H NMR data showed that the levels of 2-oxoglutarate,citrate,succinate,creatine,lactate, trimethylamine-N-oxide(TMAO),hippurate,2-hydroxy-isovaleric acid,taurine,dimethylamine (DMA),creatinine and glucose of rats urine changed after exposure,and most of these changes were more conspicuous in the combined-exposure group.These changed metabolites may be considered biomarker candidates of the combined toxicity.Furthermore,the increase of the toxic effects induced by combined exposure to TCDD and PCBs are related to the injury of mitochondrial function,reductions energy metabolism in tricarboxylic acid cycle(TAC) and perturbations in the metabolism of glucose,lipid and amino acids
Finally,the possible modes and mechanisms of combined effects of TCDD and PCBs were investigated.SD rats were intragastrically administered TCDD,PCBs,or the combination daily for consecutive 12 days.After sacrificed rats,serum was used for detecting blood biochemical parameters,the tissues were used to histopathologic study,and tissue lipid peroxidation and the protein expression of cytochrome P450 1A1(CYP1A1),heat shock protein 70(HSP70) were determined.The consequence suggested that all rats of treatment groups showed significant toxicities,as evidenced by significant decreases in body weight,changes in organ coefficients and serum biochemistry parameters,and marked histological changes and tissue oxidative damage,furthermore,high expression of CYP1A1 and HSP70 in tissues.Most of these effects were more conspicuous in the combined-exposure group.These findings indicated that aryl hydrocarbon receptor-mediated the high expression of CYP1A1 elicited oxidative injuries may play an important role in the combined toxicity of TCDD and PCBs,and suggested that malondialdehyde(MDA),superoxide dismutase(SOD),glutathione peroxide(GSH-Px), CYP1A1 and HSP70 in tissue may be considered molecular biomarker candidates of the combined toxicity.In addition,the result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were complicated,being additive,synergistic or antagonistic depending on the selection of toxicity endpoints under the present experimental condition.
Based on the results of this study,the following conclusions could be made under the present experimental condition:①The metabonomics spectra of urine could be distinguished readily by different toxic mechanism using metabonomics technique.Metabonomics is a promising new technology for the combined effects study of EDs.②It was in accordance with traditional measurements for evaluating toxicity,but metabonomics method was more sensitive than traditional measurements.③Exposure alone or combined exposure to TCDD and PCBs produced significant toxicities,and the toxic effects of combined exposure were more conspicuous.④The mode of combined effects of TCDD and PCBs were complicated,and showed primarily to be additive or synergistic.⑤Using the metabonomics technique combined with conventional toxicologic technologies had selected the possible biomarkers of combined toxicity.⑥The aryl hydrocarbon receptor-mediated the high expression of CYP1A1 elicited oxidative injuries may play an important role in the combined toxicity of TCDD and PCBs.In addition,the combined toxic effects are also related to the injury of mitochondrial function, reductions energy metabolism in TAC and perturbations in the metabolism of glucose,lipid and amino acids.
首先,建立针对EDs毒性研究的代谢组学技术平台。采用2×2析因设计将20只SD大鼠随机分为4组,即对照组、PCBs单独染毒组(Aroclor1254 10 mg/kg)、TCDD单独染毒组(TCDD 10μg/kg)和联合染毒组(TCDD 10μg/kg+Aroclor1254 10 mg/kg),每组5只。灌胃染毒,每天1次,连续3 d。用代谢笼收集各组大鼠染毒前、染毒过程中每天24 h的尿液,对其进行核磁共振氢谱(~1H NMR)分析,建立特征代谢谱,采用主成分分析法(principal component analysis,PCA)对结果进行统计分析。各组间进行的PCA分析结果显示,各样本基本集中分布于得分图的椭圆形(95%置信区内)的4个区域,各染毒组大鼠尿液代谢组轨迹能够明显地与对照组分开,单独与联合染毒组大鼠尿液代谢组轨迹也能明显分开,提示各组大鼠尿液的代谢组都发生了明显的改变。本研究表明,采用代谢组学方法能够很好地表征和描述TCDD与PCBs联合暴露导致的代谢变化,并能对其复合毒性效应进行说明,表明已成功地建立了基于~1H NMR的代谢组学技术平台。代谢组学方法的灵敏性优于传统毒性评价方法,该技术用于EDs复合效应研究具有良好的应用前景。
在此基础上,本研究利用所建立的代谢组学技术平台,结合传统毒性评价方法对TCDD与PCBs联合暴露复合毒性效应进行了研究,观察联合暴露后大鼠尿液的代谢模式的变化及其与血液生化指标和组织病理学的相关性,寻找复合效应的候选生物标志物,探讨TCDD与PCBs联合暴露毒性效应机制。SD大鼠每天灌胃染毒1次,连续6 d。用代谢笼收集各组大鼠尿液,测定~1H NMR谱,并进行血清生化指标、组织病理学和组织氧化损伤检测。结果表明,各染毒组大鼠均呈现不同程度的毒性效应,表现为:体重下降、脏器系数与血清生化指标改变、组织病理学改变以及组织发生氧化损伤,这些毒性效应在联合染毒组表现更为明显。运用~1H NMR代谢组学技术研究TCDD与PCBs联合暴露对大鼠尿液代谢产物谱影响的结果表明:各组在不同染毒条件下的代谢模式可明显区分开,自染毒第一天起,各染毒组大鼠的代谢组就明显偏离对照组和染毒前的代谢组成分,且各染毒组的代谢组轨迹不同,提示其毒性作用机制可能不同。大鼠尿液~1H NMR谱改变及其相对位置与其毒性呈较强的对应关系。通过对两种评价方法结果的对比,可发现不同染毒代谢组的改变以及毒性发生发展过程中代谢组的改变均与常规毒性检测指标相符。尿样~1H NMR谱PCA分析结果表明,大鼠尿液中2-酮戊二酸、柠檬酸、琥珀酸、肌酸、乳酸、N-氧三甲胺(trimethylamine-N-oxide,TMAO)、马尿酸、2-羟异戊酸、牛磺酸、二甲胺(dimethylamine,DMA)、肌酐、葡萄糖等代谢产物水平在染毒后发生了改变,且联合暴露组的改变更明显。这些改变了的代谢成分可能成为研究复合毒性效应候选生物标志物。另外,提示联合暴露的毒性效应可能与线粒体功能受损、三羧酸循环的能量代谢异常以及葡萄糖、脂肪和氨基酸代谢紊乱有关。
进而对TCDD和PCBs联合暴露复合效应的作用模式及作用机制进行研究。SD大鼠每天灌胃染毒1次,连续12 d。染毒结束后处死大鼠,取血清测定血液生化指标,取组织进行组织病理学检查,同时检测组织脂质过氧化和组织中细胞色素P450 1A1(cytochromeP450 1A1,CYP1A1)、热休克蛋白70(heat shock protein 70,HSP70)的表达情况。结果表明,TCDD与PCBs单独及联合染毒均引起明显的毒性效应,表现为:动物体重明显下降、脏器系数与血清生化指标改变、组织病理学改变以及组织发生氧化损伤、诱导组织CYP1A1和HSP70蛋白高表达,且这些毒性效应在联合染毒组表现更为明显。通过芳烃受体诱导组织CYP1A1高表达,导致氧化损伤在TCDD和PCBs复合毒性效应中可能发挥重要的作用。此外,组织中丙二醛(malondialdehyde,MDA)、超氧化物歧化酶(superoxidedismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxide,GSH-Px)、CYP1A1和HSP70蛋白可能成为TCDD与PCBs复合毒性效应的候选分子生物标志物。析因方差分析结果表明,TCDD与PCBs的复合效应很复杂,在本实验条件下,对于不同的毒性评价终点联合作用模式表现不一,既有相加作用,又有协同和拮抗作用。
综合本研究结果,在本实验条件下,可以得到如下结论:①利用代谢组学技术可以区分不同毒性作用机制的代谢表型,代谢组学技术用于EDs复合效应研究具有良好的应用前景。②代谢组学分析结果与常规检测指标具有良好的相关性且具更多优势。③TCDD与PCBs单独及联合暴露均可引起大鼠毒性效应,联合暴露的复合毒性效应更显著。④TCDD与PCBs复合效应的作用模式复杂,主要表现为相加或协同作用。⑤利用代谢组学技术结合传统毒性评价方法筛选出了一些复合效应候选生物标志物。⑥通过芳烃受体诱导组织CYP1A1高表达,导致氧化损伤在TCDD和PCBs复合毒性效应中可能发挥重要的作用。另外,复合毒性效应可能还与线粒体功能受损、三羧酸循环中能量代谢异常以及葡萄糖、脂肪和氨基酸的代谢紊乱有关。
Endocrine disruptors(EDs) are widely dispersed environmental and food contaminants in our country that poses a great risk to the public health.They have been one of the widespread current subjects for concern in health safety throughout the world,especially their combined effects of combined exposure.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) and polychlorinated biphenyls(PCBs) are typical EDs.At present,they are one of the hot spots in the field of environmental toxicology because of their extensive disposition and coexistence in the environment,persistence,bioaccumulation,migration and high toxicity.But most researches on the toxicity and human health hazards of these EDs have focused primarily on toxicology studies conducted on individual compound,and traditional toxicity evaluating techniques remain mainstream,but the possible interactions of combined exposure to EDs have not been investigated systematically.However,considering the facts that humans are ubiquitously simultaneously exposed daily to complex mixtures of environmental contaminants in our country, assessment of the mixture effects of multiple pollutants with the new technique is of more theoretical and actual significance.Nuclear magnetic resonance(NMR)-based metabonomic approach is a newly developed technology that has been extensively applied in the studies of toxicology.Therefore,the present study was designed to assess the potential combined toxic effects of combined exposure to TCDD and PCBs with metabonomics combined with conventional toxicologic technologies,so as to explore the possible modes and mechanisms of combined effects and select the possible biomarkers of combined toxicity.The potential application of metabonomics in the combined effects study of EDs was explored.
First,the platform,based on metabonomics technique,for EDs toxicity study was established.Twenty Sprague-Dawley rats were subjected to 2×2 factorial experimental design and assigned randomly into four groups of five rats each group,including the control group,the PCBs exposure group,the TCDD exposure group,and the combined-exposure group.Rats were intragastrically administered vehicle(olive oil),PCBs(Aroclor1254,10 mg/kg),TCDD(10μg/kg),or the combination(10μg/kg TCDD+10 mg/kg Aroclor1254),once a day for consecutive 3 days.Rats were housed in metabolism cages and the 24 hour urinary samples of each rat were collected before and after exposure and its hydrogen nuclear magnetic resonance (~1H NMR) spectra were measured,spectral characteristics for each group were summarized and the data were analyzed by principal component analysis(PCA).Based on the results from PCA in all groups,the samples were primarily distributed in four regions of the scoring oval(95% confidence intervals).The urine metabonomic trajectory of all exposure groups animals could obviously separated with that of control animals,and there were separated between the exposure to TCDD or PCBs group and the combined-exposure group,which suggested that all groups had a distinct metabonomic spectra.The results of this partial study suggest that metabonomic techniques can be used to characterize the metabolic consequence combined exposure to TCDD and PCBs,to elucidate the combined toxic effects and mechanism,that the platform based on metabonomics technique has been successfully established.Metabonomics technology can be proved more sensitive than traditional method for toxicity evaluation.Metabonomics is a promising new technology for the combined effects study of EDs.
Secondly,using the metabonomics technique combined with conventional toxicologic technologies to investigate the potential combined toxic effects of combined exposure to TCDD and PCBs,to observe the relationship of the metabonomic pattern of rat urine with blood biochemical indices and histopathology and select the possible biomarker candidates of combined toxicity,to explore the toxic effect mechanism of combined exposure.SD rats were intragastrically administered TCDD,PCBs,or the combination daily for consecutive 6 days.The 24 hour urinary samples of each rat were collected before and after exposure and its nuclear magnetic resonance spectra were measured,the serum biochemical analysis,histopathology examination and tissue oxidative damage detection were taken.The results showed that all treatment groups produced different degree toxicities,as characterized by losses in body weight, changes in organ coefficients and serum biochemistry parameters,histological changes and tissue oxidative damage.Most of these effects were more remarkable in the combined-exposure group.The ~1H NMR spectroscopic and pattern recognition methods were used to detect alteration of the urine metabolite expression profile of combined exposure to TCDD and PCBs. Results showed that all treatment groups could be readily distinguished in the PCA analysis diagram without overlap,and just after exposure,the urine metabonomics trajectory biased from that of the controls or pre-exposure.It was well in agreement with the toxic injury differentia of differently treated rats that the metabonomic spectra of urine from these rats could also be distinguished easily from each other.The result of rat urine metabonomic pattern change was in accordance with that of traditional toxicity evaluation.The PCA analysis of urine ~1H NMR data showed that the levels of 2-oxoglutarate,citrate,succinate,creatine,lactate, trimethylamine-N-oxide(TMAO),hippurate,2-hydroxy-isovaleric acid,taurine,dimethylamine (DMA),creatinine and glucose of rats urine changed after exposure,and most of these changes were more conspicuous in the combined-exposure group.These changed metabolites may be considered biomarker candidates of the combined toxicity.Furthermore,the increase of the toxic effects induced by combined exposure to TCDD and PCBs are related to the injury of mitochondrial function,reductions energy metabolism in tricarboxylic acid cycle(TAC) and perturbations in the metabolism of glucose,lipid and amino acids
Finally,the possible modes and mechanisms of combined effects of TCDD and PCBs were investigated.SD rats were intragastrically administered TCDD,PCBs,or the combination daily for consecutive 12 days.After sacrificed rats,serum was used for detecting blood biochemical parameters,the tissues were used to histopathologic study,and tissue lipid peroxidation and the protein expression of cytochrome P450 1A1(CYP1A1),heat shock protein 70(HSP70) were determined.The consequence suggested that all rats of treatment groups showed significant toxicities,as evidenced by significant decreases in body weight,changes in organ coefficients and serum biochemistry parameters,and marked histological changes and tissue oxidative damage,furthermore,high expression of CYP1A1 and HSP70 in tissues.Most of these effects were more conspicuous in the combined-exposure group.These findings indicated that aryl hydrocarbon receptor-mediated the high expression of CYP1A1 elicited oxidative injuries may play an important role in the combined toxicity of TCDD and PCBs,and suggested that malondialdehyde(MDA),superoxide dismutase(SOD),glutathione peroxide(GSH-Px), CYP1A1 and HSP70 in tissue may be considered molecular biomarker candidates of the combined toxicity.In addition,the result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were complicated,being additive,synergistic or antagonistic depending on the selection of toxicity endpoints under the present experimental condition.
Based on the results of this study,the following conclusions could be made under the present experimental condition:①The metabonomics spectra of urine could be distinguished readily by different toxic mechanism using metabonomics technique.Metabonomics is a promising new technology for the combined effects study of EDs.②It was in accordance with traditional measurements for evaluating toxicity,but metabonomics method was more sensitive than traditional measurements.③Exposure alone or combined exposure to TCDD and PCBs produced significant toxicities,and the toxic effects of combined exposure were more conspicuous.④The mode of combined effects of TCDD and PCBs were complicated,and showed primarily to be additive or synergistic.⑤Using the metabonomics technique combined with conventional toxicologic technologies had selected the possible biomarkers of combined toxicity.⑥The aryl hydrocarbon receptor-mediated the high expression of CYP1A1 elicited oxidative injuries may play an important role in the combined toxicity of TCDD and PCBs.In addition,the combined toxic effects are also related to the injury of mitochondrial function, reductions energy metabolism in TAC and perturbations in the metabolism of glucose,lipid and amino acids.
引文
[1]Baker VA.Endocrine disrupters-testing strategies to assess human hazard.Toxicol In Vitro,2001,15(4-5):413-419.
[2]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[3]Friedmann AS.Atrazine inhibition of testosterone production in rat males following peripubertal exposure.Reprod Toxicol,2002,16(3):275-279.
[4]Iwasaki T,Miyazaki W,Takeshita A,Kuroda Y,Koibuchi N.Polychlorinated biphenyls suppress thyroid hormone-induced transactivation.Biochem Biophys Res Commun,2002,299(3):384-388.
[5]Gunnarsson D,Nordberg G,Lundgren P,Selstam G.Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats.Toxicology,2003,183(1-3):57-63.
[6]Hsu PC,Li MH,Guo YL.Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats.Toxicology,2003,187(2-3):117-126.
[7]Suzuki T,Mizuo K,Nakazawa H,Funae Y,Fushiki S,Fukushima S,Shirai T,Narita M.Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice:enhancement of the methamphetamine-induced abuse state.Neuroscience,2003,117(3):639-644.
[8]Greim HA.The Endocrine and Reproductive System:Adverse Effects of Hormonally Active Substances?Pediatrics,2004,113(4):1070-1075.
[9]Karcher W.Recent trends and developments in the EU in the environmental control and management of chemicals.Ecotoxicol Environ Saf,1998,40(1-2):97-102.
[10]Kavlock RJ.Overview of endocrine disruptor research activity in the United States.Chemosphere,1999,39(8):1227-1236.
[11]Reiter LW,DeRosa C,Kavlock RJ,Lucier G,Mac MJ,Melillo J,Melnick RL,Sinks T,Walton BT.The U.S.federal framework for research on endocrine disruptors and an analysis of research programs supported during fiscal year 1996.Environ Health Perspect,1998,106(3):105-113.
[12]Shelby MD,Newbold RR,Tully DB,Chae K,Davis VL.Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays.Environ Health Perspect,1996,104(12):1296-1300.
[13]Gray Jr LE,Kelce WR,Wiese T,Tyl R,Gaido K,Cook J,Klinefelter G,Desaulniers D,Wilson E,Zacharewski T,Waller C,Foster P,Laskey J,Reel J,Giesy J,Laws S,McLachlan J,Breslin W,Cooper R,Di Giulio R,Johnson R,Purdy R,Mihaich E,Safe S,Colborn T.Endocrine Screening Methods Workshop report:detection of estrogenic and androgenic hormonal and antihormonal activity for chemicals that act via receptor or steroidogenic enzyme mechanisms.Reprod Toxicol,1997,11(5):719-750.
[14]Nishikawa J,Saito K,Goto J,Dakeyama F,Matsuo M,Nishihara T.New screening methods for chemicals with hormonal activities using interaction of nuclear hormone receptor with coactivator.Toxicol Appl Pharmacol,1999,154(1):76-83.
[15]Coen M,Hong YS,Clayton TA,Rohde CM,Pearce JT,Reily MD,Robertson DG,Holmes E,Lindon JC,Nicholson JK.The mechanism of galactosamine toxicity revisited;a metabonomic study.J Proteome Res,2007,6(7):2711-2719.
[16]Lindon JC,Holmes E,Nicholson JK.Metabonomics in pharmaceutical R&D.FEBS J,2007,274(5):1140-1151.
[17]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[18]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[19]Lindon JC,Nicholson JK,Holmes E,Antti H,Bollard ME,Keun H,Beckonert O,Ebbels TM,Reily MD,Robertson D,Stevens GJ,Luke P,Breau AP,Cantor GH,Bible RH,Niederhauser U,Senn,H Schlotterbeck G,Sidelmann UG,Laursen SM,Tymiak A,Car BD,Lehman-McKeeman L,Colet JM,Loukaci A,Thomas C.Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.Toxicol Appl Pharmacol,2003,187(3):137-146.
[20]Nicholson JK,Lindon JC,Holmes E.‘Metabonomics’:understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[21]Nicholson JK,Connelly J,Lindon JC,Holmes.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[22]Aas E,Baussant T,Balk L,Liewenborg B,Andersen OK.PAH metabolites in bile,cytochrome P4501A and DNA adducts as environmental risk parameters for chronic oil exposure:a laboratory experiment with Atlantic cod.Aquat Toxicol,2000,51(2):241-258.
[23]Kostka G.The use of biomarkers in the assessment of health risk from environmental exposure to chemical carcinogens.Rocz Panstw Zakl Hig,2003,54(S1):30-31.
[24]Borras M,Nadal J.Biomarkers of genotoxicity and other end-points in an integrated approach to environmental risk assessment.Mutagenesis,2004,19:165-168.
[25]Poland A,Knutson JC.2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons:examination of the mechanism of toxicity.Annu Rev Pharmacol Toxicol,1982,22:517-554.
[26]Viel J F,Arveux P,Baverel J,Cahn J Y.Soft-tissue sarcoma and non-hodgkin's lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels.Am J Epidemiol,2000,152(1):13-19.
[27]Domingo JL,Agramunt MC,Nadal M,Schuhmacher M,Corbella J.Health risk assessment of PCDD/PCDF exposure for the population living in the vicinity of a municipal waste incinerator.Arch Environ Contam Toxicol,2002,43(4):461-465.
[29]Cole P,Trichopoulos D,Pastides H,Starr T,Mandel JS.Dioxin and cancer:a critical review.Regul Toxicol Pharmacol,2003,38(3):378-388.
[29]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[30]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[31]Safe SH.Polychlorinated biphenyls(PCBs):environmental impact,biochemical and toxic responses,and implications for risk assessment.Crit Rev Toxicol,1994,24(2):87-149.
[32]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini D N,Kanagaraj P,Stanley A J,Srinivasan N,Balasubramanian K,Aruldhas M M,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclor 1254) induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[33]Nagayama J,Tsuji H,Iida T,Nakagawa R,Matsueda T,Hirakawa H,Yanagawa T,Fukushige J,Watanabe T.Immunologic effects of perinatal exposure to dioxins,PCBs and organochlorine pesticides in Japanese infants.Chemosphere,2007;67(9):S393-398.
[1]Baker VA.Endocrine disrupters--testing strategies to assess human hazard.Toxicol In Vitro,2001,15(4-5):413-419.
[2]Larsen JC.Risk assessments of polychlorinated dibenzo-p-dioxins,polychlorinated dibenzofurans,and dioxin-like polychlorinated biphenyls in food.Mol Nutr Food Res,2006,50(10):885-896.
[3]Dahl P,Lindstrom G,Wiberg K,Rappe C.Absorption of polychlorinated biphenyls,dibenzo-p-dioxins and dibenzofurans by breast-fed infants.Chemosphere,1995,30(12):2297-2306.
[4]Leung HW,Wendling JM,Orth R,Hileman F,Paustenbach DJ.Relative distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatic and adipose tissues.Toxicol Lett,1990,50(2-3):275-282.
[5]Pohjanvirta R,Vartiainen T,Uusi-Rauva A,Monkkonen J,Tuomisto J.Tissue distribution,metabolism,and excretion of 14C-TCDD in a TCDD-susceptible and a TCDD-resistant rat strain.Pharmacol Toxicol,1990,66(2):93-100.
[6]Kreuzer PE,Csanady GA,Baur C,Kessler W,Papke O,Greim H,Filser JG.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) and congeners in infants.A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.Arch Toxicol,1997,71(6):383-400.
[7]Clewell HJ,Robinan Gentry P,Covington TR,Sarangapani R,Teeguarden JG Evaluation of the potential impact of age-and gender-specific pharmacokinetic differences on tissue dosimetry.Toxicol Sci,2004,79(2):381-393.
[8]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[9]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[10]Tuomisto JT,Pohjanvirta R,Unkila M,Tuomisto J.TCDD-induced anorexia and wasting syndrome in rats:effects of diet-induced obesity and nutrition.Pharmacol Biochem Behav,1999,62(4):735-742.
[11]Coenraads PJ,Olie K,Tang NJ.Blood lipid concentrations of dioxins and dibenzofurans causing chloracne.Br J Dermatol,1999,141(4):694-697.
[12]Neuberger M,Kundi M,Jager R.Chloracne and morbidity after dioxin exposure(preliminary results). Toxicol Lett,1998,96-97:347-350.
[13]Sweeney MH,Mocarelli P.Human health effects after exposure to 2,3,7,8-TCDD.Food Addit Contam,2000,17(4):303-316.
[14]Connell BJ,Singh A,Chu I.Interaction of PCB congeners and 2,3,7,8-TCDD in the rat liver:an electron microscope study.J Submicrosc Cytol Pathol,1998,30(1):157-163.
[15]Walter GL,Jones PD,Giesy JP.Pathologic alterations in adult rainbow trout,oncorhynchus mykiss,exposed to dietary 2,3,7,8-tetrachlorodibenzo-p-dioxin.Aquat Toxicol,2000,50(4):287-299.
[16]刘云儒,汤乃军,任大林.2,3,7,8-四氯二苯-p-二恶英对大鼠肝脏芳香烃受体和细胞色素p4501A1mRNA的诱导.中华劳动卫生职业病杂志,2003,21(6):417-419.
[17]汤乃军,刘云儒,任大林.2,3,7,8-四氯二苯并二恶英对SD大鼠肝脏SOD、GST、MDA影响的实验研究.中国工业医学杂志,2003,16(6):335-337.
[18]Kern PA,Fishman RB,Son g W,Brown AD,Fonseca V.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on oxidative enzymes in adipocytes and liver.Toxicology,2002,171(2-3):117-125.
[19]Gannon M,Gilday D,Rifkind AB.TCDD induces CYP1A4 and CYP1A5 in chick liver and kidney and only CYP1A4,an enzyme lacking arachidonic acid epoxygenase activity,in myocardium and vascular endothelium.Toxicol Appl Pharmacol,2000,164(1):24-37.
[20]Fletcher N,Hanberg A,H(?)kansson H.Hepatic vitamin a depletion is a sensitive marker of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) exposure in four rodent species.Toxicol Sci,2001,62(1):166-175.
[21]Narasimhan TR,Craig A,Arellano L,Harper N,Howie L,Menache M,Birnbaum L,Safe S.Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cypla-1 and Cypla-2 gene expression and immunotoxicity in female B6C3F1 mice.Fundam Appl Toxicol,1994,23(4):598-607.
[22]Mitchell KA,Paige Lawrence B.Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) renders influenza virus-specific CD8~+ T cells hyporesponsive to antigen.Toxicol Sci,2003,74(1):74-84.
[23]Neff-LaFord HD,Vorderstrasse BA,Lawrence BP.Fewer CTL,not enhanced NK cells,are sufficient for viral clearance from the lungs of immunocompromised mice.Cell Immunol,2003,226(1):54-64.
[24]Camacho IA,Nagarkatti M,Nagarkatti PS.Evidence for induction of apoptosis in T cells from murine fetal thymus following perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD).Toxicol Sci,2004,78(1):96-106.
[25]Egeland GM,Sweeney MH,Fingerhu t MA,Wille KK,Schnorr TM,.Halperin WE.Total serum testosterone and gonadotropins in workers exposed to dioxin.Am J Epidemiol,1994,139(3):272-281.
[26]Li B,Liu HY,Dai LJ,Lu JC,Yang ZM,Huang L.The early embryo loss caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin may be related to the accumulation of this compound in the uterus.Reprod Toxicol,2006,21(3):301-306.
[27]Mably TA,Bjerke DL,Moore RW,Gendron-Fitzpatrick A,Peterson RE.In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin.3.Effects on spermatogenesis and reproductive capability.Toxicol Appl Pharmacol,1992,114(1):118-126.
[28]Latchoumycandane C,Chitra KC,Mathur PP.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) induces oxidative stress in the epididymis and epididymal sperm of adult rats.Arch Toxicol,2003,77(5):280-284.
[29]Brouwer A,Ahlborg UG,Van den Berg M,Birnbaum LS,Boersma ER,Bosveld B,Denison MS,Gray LE,Hagmar L,Holene E.Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants.Eur J Pharmacol,1995,293(1):1-40.
[30]Teraoka H,Dong W,Hiraga T.Zebrafish as a novel experimental model for developmental toxicology.Congenit Anom(Kyoto),2003,43(2):123-132.
[31]Ohsako S,Miyabara Y,Sakaue M,Ishimura R,Kakeyama M,Izumi H,Yonemoto J,Tohyama C.Developmental stage-specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring.Toxicol Sci,2002,66(2):283-292.
[32]Kim SY,Yang JH.Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells.Exp Mol Med,2005,37(1):58-64.
[33]Van Loveren H,Vos J,Putman E,Piersma A.Immunotoxicological consequences of perinatal chemical exposures:a plea for inclusion of immune parameters in reproduction studies.Toxicology,2003,185(3):185-191.
[34]Nyska A,Yoshizawa K,Jokinen MP,Brix AE,Sells DM,Wyde ME,Orzech DP,Kissling GE,Walker NJ.Olfactory epithelial metaplasia and hyperplasia in female harlan sprague-dawley rats following chronic treatment with polychlorinated biphenyls.Toxicol Pathol,2005,33(3):371-377.
[35]Yoshizawa K,Walker NJ,Jokinen MP,Brix AE,Sells DM,Marsh T,Wyde ME,Orzech D,Haseman JK,Nyska A.Gingival carcinogenicity in female harlan sprague-dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.Toxicol Sci,2005,83(1):405-406.
[36]Pavuk M,Michalek JE,Ketchum NS.Prostate cancer in US air force veterans of the Vietnam war.J Expo Sci Environ Epidemiol,2006,16(2):184-190.
[37]Wu Q,Ohsako S,Baba T,Miyamoto K,Tohyama C.Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on preimplantation mouse embryos.Toxicology,2002,174(2):119-129.
[38]Bertazzi PA,Consonni D,Bachetti S,Rubagotti M,Baccarelli A,Zocchetti C,Pesatori AC.Health effects of dioxin exposure:a 20-year mortality study.Am J Epidemiol,2001,153(11):1031-1044.
[39]Poland A,Palen D,Glover E.Tumour promotion by TCDD in skin of HRS/J hairless mice.Nature,1982,300(5889):271-273.
[40]Nyska A,Jokinen MP,Brix AE,Sells DM,Wyde ME,Orzech D,Haseman JK,Flake G,Walker NJ.Exocrine pancreatic pathology in female harlan sprague-dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.Environ Health Perspect,2004,112(8):903-909.
[41]Yoshizawa K,Marsh T,Foley JF,Cai B,Peddada S,Walker NJ,Nyska A.Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female harlan sprague-dawley rats.Toxicol Sci,2005,85(1):594-606.
[42]Signorini S,Gerthoux PM,Dassi C,Cazzaniga M,Brambilla P,Vincoli N,Mocarelli P.Environmental exposure to dioxin:the Seveso experience.Andrologia,2000,32(4-5):263-270.
[43]Jokinen MP,Walker NJ,Brix AE,Sells DM,Haseman JK,Nyska A.Increase in cardiovascular pathology in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,3',4,4',5-pentachlorobiphenyl.Cardiovasc Toxicol,2003,3(4):299-310.
[44]Neuberger M,Rappe C,Bergek S,Cai H,Hansson M,Jager R,Kundi M,Lim CK,Wingfors H,Smith AG.Persistent health effects of dioxin contamination in herbicide production.Environ Res,1999,81(3):206-214.
[45]Baba T,Mimura J,Nakamura N,Harada N,Yamamoto M,Morohashi K,Fujii-Kuriyama Y.Intrinsic function of the aryl hydrocarbon(dioxin) receptor as a key factor in female reproduction.Mol Cell Biol,2005,25(22):10040-10051.
[46]Korkalainen M,Tuomisto J,Pohjanvirta R.Identification of novel splice variants of ARNT and ARNT2 in the rat.Biochem Biophys Res Commun,2003,303(4):1095-1100.
[47]Pongratz I,Mason GG,Poellinger L.Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor.Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity.J Biol Chem,1992,267(19):13728-13734.
[48]Chapman-Smith A,Lutwyche JK,Whitelaw ML.Contribution of the per/arnt/sim(PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators.J Biol Chem,2004,279(7):5353-5362.
[49]Andersson P,Ridderstad A,McGuire J,Pettersson S,Poellinger L,Hanberg A.A constitutively active aryl hydrocarbon receptor causes loss of peritoneal Bl cells.Biochem Biophys Res Commun,2003,302(2):336-341.
[50]Nebert DW,Dalton TP,Okey AB,Gonzalez FJ.Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.J Biol Chem,2004,279(23):23847-23850.
[51]Mimura J,Fujii-Kuriyama Y.Functional role of AhR in the expression of toxic effects by TCDD.Biochim Biophys Acta,2003,1619(3):263-268.
[52]Knerr S,Schaefer J,Both S,Mally A,Dekant W,Schrenk D.2,3,7,8-tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells.Mol Nutr Food Res,2006,50(4-5):378-384.
[53]Backlund M,Ingelman-Sundberg M.Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases.Cell Signal,2005,17(1):39-48.
[54]Enan E,Moran F,VandeVoort CA,Stewart DR,Overstreet JW,Lasley BL.Mechanism of toxic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in cultured human luteinized granulosa cells.Reprod Toxicol,1996,10(6):497-508.
[55]Tan Z,Chang X,Puga A,Xia Y.Activation of mitogen-activated protein kinases(MAPKs) by aromatic hydrocarbons:role in the regulation of aryl hydrocarbon receptor(AHR) function.Biochem Pharmacol,2002,64(5-6):771-780.
[56]Abbott BD,Probst MR.Developmental expression of two members of a new class of transcription factors:Ⅱ.Expression of aryl hydrocarbon receptor nuclear translocator in the C57BL/6N mouse embryo.Dev Dyn,1995,204(2):144-155.
[57]Yu ML,Guo YL,Hsu CC,Rogan WJ.Menstruation and reproduction in women with polychlorinated biphenyl(PCB) poisoning:long-term follow-up interviews of the women from the Taiwan Yucheng cohort.Int J Epidemiol,2000,29(4):672-677.
[58]Bernard A,Hermans C,Broeckaert F,De Poorter G,De Cock A,Houins G.Food contamination by PCBs and dioxins.Nature,1999,401(6750):231-232.
[59]Litten S,Fowler B,Luszniak D.Identification of a novel PCB source through analysis of 209 PCB congeners by US EPA modified method 1668.Chemosphere,2002,46(9-10):1457-1459.
[60]Sandau CD,Ayotte P,Dewailly E,Duffe J,Norstrom RJ.Pentachlorophenol and hydroxylated polychlorinated biphenyl metabolites in umbilical cord plasma of neonates from coastal populations in Quebec.Environ Health Perspect,2002,110(4):411-417.
[61]Soechitram SD,Athanasiadou M,Hovander L,Bergman A,Sauer PJ.Fetal exposure to PCBs and their hydroxylated metabolites in a Dutch cohort.Environ Health Perspect,2004,112(11):1208-1212.
[62]Carlsen E,Giwercman A,Keiding N,Skakkebaek NE.Evidence for decreasing quality of semen during past 50 years.BMJ,1992,305(6854):609-613.
[63]Wolff MS.Occupational exposure to polychlorinated biphenyls(PCBs).Environ Health Perspect,1985,60:133-138.
[64]Haraguchi K,Hirose Y,Masuda Y,Kato Y,Kimura R.Metabolism of 3,3',4,4',5-penta-and 2,2',3,3',4,4'-hexachlorobiphenyls in rats.Fukuoka Igaku Zasshi,1999,90(5):210-219.
[65]Ross G.The public health implications of polychlorinated biphenyls(PCBs) in the environment.Ecotoxicol Environ Saf,2004,59(3):275-291.
[66]Krishnamoorthy G,Murugesan P,Muthuvel R,Gunadharini DN,Vijayababu MR,Arunkumar A,Venkataraman P,Aruldhas MM,Arunakaran J.Effect of Aroclor1254 on Sertoli cellular antioxidant system,androgen binding protein and lactate in adult rat in vitro.Toxicology,2005,212(2-3):195-205.
[67]Murugesan P,Muthusamy T,Balasubramanian K,Arunakaran J.Studies on the protective role of vitamin C and E against polychlorinated biphenyl(Aroclor1254)--induced oxidative damage in Leydig cells.Free Radic Res,2005 a,39(11):1259-1272.
[68]Murugesan P,Senthilkumar J,Balasubramanian K,Aruldhas MM,Arunakaran J.Impact of polychlorinated biphenyl Aroclor1254 on testicular antioxidant system in adult rats.Human and Experimental Toxicology,2005 b,24:61-66.
[69]Murugesan P,Balaganesh M,Balasubramanian K,Arunakaran J.Effects of polychlorinated biphenyl(Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells.J Endocrinol,2007,192(2):325-338.
[70]Murugesan P,Muthusamy T,Balasubramanian K,Arunakaran J.Polychlorinated biphenyl(Aroclor 1254) inhibits testosterone biosynthesis and antioxidant enzymes in cultured rat Leydig cells.Reprod Toxicol,2008,25(4):447-454.
[71]Hertz-Picciotto I,Charles MJ,James RA,Keller JA,Willman E,Teplin S.In utero polychlorinated biphenyl exposures in relation to fetal and early childhood growth.Epidemiology,2005,16(5):648-656.
[72]Knerr S,Schrenk D.Carcinogenicity of“non-dioxinlike”polychlorinated biphenyls.Crit Rev Toxicol, 2006,36(9):663-694.
[73]Guo YL,Yu ML,Hsu CC,Rogan WJ.Chloracne,goiter,arthritis,and anemia after polychlorinated biphenyl poisoning:14-year follow-Up of the Taiwan Yucheng cohort.Environ Health Perspect,1999,107(9):715-719.
[74]Kimbrough RD,Krouskas C.Polychlorinated biphenyls,TEQs,children,and data analysis.Vet Hum Toxicol,2002,44(6):354-357.
[75]Kimbrough RD,Krouskas CA.Human exposure to polychlorinated biphenyls and health effects:a critical synopsis.Toxicol Rev,2003,22(4):217-233.
[76]Kimbrough RD,Doemland ML,LeVois ME.Mortality in male and female capacitor workers exposed to polychlorinated biphenyls.J Occup Environ Med,1999,41(3):161-171.
[77]Kimbrough RD,Doemland ML,Krouskas CA.Analysis of research studying the effects of polychlorinated biphenyls and related chemicals on neurobehavioral development in children.Vet Hum Toxicol,2001,43(4):220-228.
[78]Kilic N,Sandal S,Colakoglu N,Kutlu S,Seyran A,Yilmaz B.Endocrine disruptive effects of polychlorinated biphenyls on the thyroid gland in female rats.Tohoku J Exp Med,2005,206(4):327-332.
[79]Khan MA,Hansen LG Ortho-substituted polychlorinated biphenyl(PCB) congeners(95 or 101) decrease pituitary response to thyrotropin releasing hormone.Toxicol Lett,2003,144(2):173-182.
[80]Hsu PC,Huang W,Yao WJ,Wu MH,Guo YL,Lambert GH.Sperm changes in men exposed to polychlorinated biphenyls and dibenzofurans.JAMA,2003 a,289(22):2943-2944.
[81]Osius N,Karmaus W,Kruse H,Witten J.Exposure to polychlorinated biphenyls and levels of thyroid hormones in children.Environ Health Perspect,1999,107(10):843-849.
[82]Gupta C.Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals.Proc Soc Exp Biol Med,2000,224(2):61-68.
[83]Zhang C,Fang C,Liu L,Xia G,Qiao H.Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens.J Environ Sci Health A Tox Hazard Subst Environ Eng,2002,37(4):509-519.
[84]Hsu PC,Li MH,Guo YL.Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats.Toxicology,2003 b,187(2-3):117-126.
[85]Andric SA,Kostic TS,StojilkoVic SS,Kovacevic RZ.Inhibition of rat testicular androgenesis by a polychlorinated biphenyl mixture Aroclorl248.Biol Reprod,2000,62(6):1882-1888.
[86]Nixon A,Benghuzzi H,Cason Z.Morphometric evaluation of ovarian tissue exposed to PCB conventionally and in a sustained manner.Biomed Sci Instrum,2003,39:434-439.
[87]Ruby S,Mendoza LT,Fournier M,Brousseau P,Degas V.Reproductive system impairment of mice fed diets containing beluga whale blubber from the St Lawrence estuary and arctic populations.J Toxicol Environ HealthA,2003,66(11):1073-1085.
[88]Kholkute SD,Rodriguez J,Dukelow WR.Effects of polychlorinated biphenyls(PCBs) on in vitro fertilization in the mouse.Reprod Toxicol,1994,8(1):69-73.
[89]Wojtowicz A,Ropstad E,Gregoraszczuk E.Estrous cycle dependent changes in steroid secretion by pig ovarian cells in vitro to polychlorinated biphenyl(PCB 153).Endocr Regul,2001,35(4):223-228.
[90]Mol NM,Sorensen N,Weihe P,Andersson AM,Jorgensen N,Skakkebaek NE,Keiding N,Grandjean P.Spermaturia and serum hormone concentrations at the age of puberty in boys prenatally exposed to polychlorinated biphenyls.Eur J Endocrinol,2002,146(3):357-363.
[91]Guo YL,Hsu PC,Hsu CC,Lambert GH.Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans.Lancet,2000,356(9237):1240-1241.
[92]Harper N,Howie L,Connor K,Dickerson R,Safe S.Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice.Toxicology,1993,85(2-3):123-135.
[93]Dewailly E,Ayotte P,Bruneau S,Gingras S,Belles-Isles M,Roy R.Susceptibility to infections and immune status in Inuit infants exposed to organochlorines.Environ Health Perspect,2000,108(3):205-211.
[94]Gustavsson P,Hogstedt C.A cohort study of Swedish capacitor manufacturing workers exposed to polychlorinated biphenyls(PCBs).Am J Ind Med,1997,32(3):234-239.
[95]Sheikh MS,Ramirez A,Emmett M,Santa Ana C,Schiller LR,Fordtran JS.Role of vitamin D-dependent and vitamin D-independent mechanisms in absorption of food calcium.J Clin Invest,1988,81(1):126-132.
[96]Fischbein A,Wolff MS,Lilis R,Thornton J,Selikoff IJ.Clinical findings among PCB-exposed capacitor manufacturing workers.Ann N Y Acad Sci,1979,320:703-715.
[97]Patandin S,Lanting CI,Mulder PG,Boersma ER,Sauer PJ,Weisglas-Kuperus N.Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age.J Pediatr,1999,134(1):33-41.
[98]Van Birgelen AP,Smit EA,Kampen IM,Groeneveld CN,Fase KM,Van der Kolk J,Poiger H,Van den Berg M,Koeman JH,Brouwer A.Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism:use in risk assessment.Eur J Pharmacol,1995,293(1):77-85.
[99]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[100]Garner CE,Jefferson WN,Burka LT,Matthews HB,Newbold RR.In vitro estrogenicity of the catechol metabolites of selected polychlorinated biphenyls.Toxicol Appl Pharmacol,1999,154(2):188-197.
[101]Portigal CL,Cowell SP,Fedoruk MN,Butler CM,Rennie PS,Nelson CC.Polychlorinated biphenyls interfere with androgen-induced transcriptional activation and hormone binding.Toxicol Appl Pharmacol,2002,179(3):185-194.
[102]Kodavanti PR,Tilson HA.Neurochemical effects of environmental chemicals:in vitro and in vivo correlations on second messenger pathways.Ann N Y Acad Sci,2000,919:97-105.
[103]Bae J,Stuenkel EL,Loch-Caruso R.Stimulation of oscillatory uterine contraction by the PCB mixture Aroclor 1242 may involve increased[Ca~(2+)]i through voltage-operated calcium channels.Toxicol Appl Pharmacol,1999,155(3):261-272.
[104]Thompson CJ,Ross SM,Gaido KW.Di(w-Butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism.Endocrinology,2004,145(3):1227-1237.
[105]Song WC.Biochemistry and reproductive endocrinology of estrogen sulfotransferase.Ann N Y Acad Sci,2001,948:43-50.
[106]WHO.Combination Effects in Chemical Carcinogesis.VCH Publishern,New york,1988,5-20
[107]Broderius SJ,kahi MD,Hoglund MD.Use of joint toxic response to define the primary mode of toxic action for diverse industrial organic chemicals.Environmental Toxicology and Chemistry,1995,14(9):1591-1605.
[108]Groten JP.Mixtures and interactions.Food Chem Toxicol,2000,38(1 Suppl):S65-71.
[109]Chu I,Lecavalier P,Hakansson H,Yagminas A,Valli VE,Poon R,Feeley M.Mixture effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls congeners in rats.Chemosphere,2001,43(4-7):807-814.
[110]Wade MG,Foster WG,Younglai EV,McMahon A,Leingartner K,Yagminas A,Blakey D,Fournier M,Desaulniers D,Hughes CL.Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats:systemic,immune,and reproductive effects.Toxicol Sci,2002,67(1):131-143.
[111]Desaulniers D,Leingartner K,Musicki B,Yagminas A,Xiao GH,Cole J,Marro L,Charbonneau M,Tsang BK.Effects of postnatal exposure to mixtures of non-ortho-PCBs,PCDDs,and PCDFs in prepubertal female rats.Toxicol Sci,2003,75(2):468-480.
[112]彭双清,郝卫东,伍一军.毒理学替代法[M].第一版,北京:军事医学科学院出版社,2009,519-528.
[113]Devaux PG,Horning MG,Hill RM,Horning EC.O-benzyloximes:derivatives for the study of ketosteroids by gas chromatography.Application to urinary steroids of the newborn human.Anal Biochem,1971,41(1):70-82.
[114]Fiehn O.Metabolic networks of Cucurbita maxima phloem.Phytochemistry,2003,62(6):875-886.
[115]Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[116]Nicholson JK,Connelly J,Lindon JC,Holmes E.Metabonomics:a platform,for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[117]German JB,Bauman DE,Burrin DG,Failla ML,Freake HC,King JC,Klein S,Milner JA,Pelto GH,Rasmussen KM,Zeisel SH.Metabolomics in the opening decade of the 21st century:building the roads to individualized health.J Nutr,2004,134(10):2729-2732.
[118]Jonsson P,Bruce SJ,Moritz T,Trygg J,Sjostrom M,Plumb R,Granger J,Maibaum E,Nicholson JK,Holmes E,Antti H.Extraction,interpretation and validation of information for comparing samples in metabolic LC/MS data sets.Analyst,2005,130(5):701-707.
[119]Sandusky P,Raftery D.Use of semiselective TOCSY and the pearson correlation for the metabonomic analysis of biofluid mixtures:application to urine.Anal Chem,2005,77(23):7717-7723.
[120]Wagner S,Scholz K,Sieber M,Kellert M,Voelkel W.Tools in metabonomics:an integrated validation approach for LC-MS metabolic profiling of mercapturic acids in human urine.Anal Chem,2007,79(7):2918-2926.
[121]Sitter B,Lundgren S,Bathen TF,Halgunset J,Fjosne HE,Gribbestad IS.Comparison of HR MAS MR spectroscopic profiles of breast cancer tissue with clinical parameters.NMR Biomed,2006,19(1):30-40.
[122]Yang J,Xu G,Zheng Y,Kong H,Pang T,Lv S,Yang Q.Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases.J Chromatogr B Analyt Technol Biomed Life Sci,2004,813(1-2):59-65.
[123]Bollard ME,Stanley EG,Lindon JC,Nicholson JK,Holmes E.NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition.NMR Biomed,2005,18(3):143-162.
[124]Dettmer K,Aronov PA,Hammock BD.Mass spectrometry-based metabolomics.Mass Spectrom Rev,2007,26(1):51-78.
[125]Beckwith-Hall BM,Thompson NA,Nicholson JK,Lindon JC,Holmes E.A metabonomic investigation of hepatotoxicity using diffusion-edited 1H NMR spectroscopy of blood serum.Analyst,2003,128(7):814-818.
[126]Tang H,Wang Y,Nicholson JK,Lindon JC.Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma.Anal Biochem,2004,325(2):260-272.
[127]Webb-Robertson,BJ Lowry DF,Jarman KH,Harbo SJ,Meng QR,Fuciarelli AF,Pounds JG,Lee KM.A study of spectral integration and normalization in NMR-based metabonomic analyses.J Pharm Biomed Anal,2005,39(3-4):830-836.
[128]Aranibar N,Ott KH,Roongta V,Mueller L.Metabolomic analysis using optimized NMR and statistical methods.Anal Biochem,2006,355(1):62-70.
[129]Craig A,Cloarec O,Holmes E,Nicholson JK,Lindon JC.Scaling and normalization effects in NMR spectroscopic metabonomic data sets.Anal Chem,2006,78(7):2262-2267.
[130]Halouska S,Powers R.Negative impact of noise on the principal component analysis of NMR data.J Magn Reson,2006,178(1):88-95.
[131]van den Berg RA,Hoefsloot HC,Westerhuis JA,Smilde AK,van der Werf MJ.Centering,scaling,and transformations:improving the biological information content of metabolomics data.BMC Genomics,2006,7:142-156.
[132]Weckwerth W,Morgenthal K.Metabolomics:from pattern recognition to biological interpretation.Drug Discov Today,2005,10(22):1551-1558.
[133]Brauer DJ.A method for pattern recognition.Res Theory Nurs Pract,2006,20(4):277-289.
[134]Stoyanova R,Brown TR.NMR spectral quantitation by principal component analysis.NMR Biomed,2001,14(4):271-277.
[135]Wang Y,Bollard ME,Keun H,Antti H,Beckonert O,Ebbels TM,Lindon JC,Holmes E,Tang H,Nicholson JK.Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning 1H nuclear magnetic resonance spectroscopy of liver tissues.Anal Biochem,2003,323(1):26-32.
[136]Gavaghan CL,Wilson ID,Nicholson JK.Physiological variation in metabolic phenotyping and functional genomic studies:use of orthogonal signal correction and PLS-DA.FEBS Lett,2002,530(1-3):191-196.
[137]Eriksson L,Antti H,Gottfries J,Holmes E,Johansson E,Lindgren F,Long I,Lundstedt T,Trygg J,Wold S.Using chemometrics for navigating in the large data sets of genomics,proteomics,and metabonomics(gpm).Anal Bioanal Chem,2004,380(3):419-429.
[138]Holmes E,Nicholson JK,Tranter G.Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks.Chem Res Toxicol,2001,14(2):182-191.
[139]Lindon JC,Nicholson JK,Holmes E,Antti H,Bollard ME,Keun H,Beckonert O,Ebbels TM,Reily MD,Robertson D,Stevens GJ,Luke P,Breau AP,Cantor GH,Bible RH,Niederhauser U,Senn,H Sehlotterbeck G,Sidelmann UG,Laursen SM,Tymiak A,Car BD,Lehman-McKeeman L,Colet JM,Loukaci A,Thomas C.Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.Toxicol Appl Pharmacol,2003,187(3):137-146.
[140]Williams RE,Lock EA.Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat.Toxicology,2005,207(1):35-48.
[141]廖艳,彭双清,颜贤忠.异烟肼肝毒性的代谢组学特征研究.中国新药杂志,2007;16(4):288-292.
[142]Idborg-Bjorkman H,Edlund PO,Kvalheim OM,Schuppe-Koistinen I,Jacobsson SP.Screening of biomarkers in rat urine using LC/electrospray ionization-MS and two-way data analysis.Anal Chem,2003,75(18):4784-4792.
[143]Soga T,Baran R,Suematsu M,Ueno Y,Ikeda S,Sakurakawa T,Kakazu Y,Ishikawa T,Robert M,Nishioka T,Tomita M.Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.J Biol Chem,2006,281(24):16768-16776.
[144]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[145]Yang J,Zhao X,Liu X,Wang C,Gao P,Wang J,Li L,Gu J,Yang S,Xu G.High performance liquid chromatography-mass spectrometry for metabonomics:potential biomarkers for acute deterioration of liver function in chronic hepatitis B.J Proteome Res,2006,5(3):554-561.
[146]Lindon JC,Holmes E,Nicholson JK.Metabonomics:systems biology in pharmaceutical research and development.Curr Opin Mol Ther,2004,6(3):265-272.
[147]Lindon JC,Keun HC,Ebbels TM,Pearce JM,Holmes E,Nicholson JK.The Consortium for Metabonomic Toxicology(COMET):aims,activities and achievements.Pharmacogenomics,2005,6(7):691-699.
[148]Plumb RS,Stumpf CL,Granger JH,Castro-Perez J,Haselden JN,Dear GJ.Use of liquid chromatography/time-of-flight mass spectrometry and multivariate statistical analysis shows promise for the detection of drug metabolites in biological fluids.Rapid Commun Mass Spectrom,2003,17(23):2632-2638.
[149]Robertson DG,Reily MD,Sigler RE,Wells DF,Paterson DA,Braden TK.Metabonomics:evaluation of nuclear magnetic resonance(NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants.Toxicol Sci,2000,57(2):326-337.
[150]Shockcor JP,Holmes E.Metabonomic applications in toxicity screening and disease diagnosis.Curr Top Med Chem,2002,2(1):35-51.
[151]Gartland KP,Bonner FW,Nicholson JK.Investigations into the biochemical effects of region-specific nephrotoxins.Mol Pharmacol,1989,35(2):242-250.
[1]Poland A,Knutson JC.2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons:examination of the mechanism of toxicity.Annu Rev Pharmacol Toxicol,1982,22:517-554.
[2]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini DN,Kanagaraj P,Stanley AJ,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclor1254)induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[3]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose- and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[4]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[5]Ivosev G,Burton L,Bonner R.Dimensionality reduction and visualization in principal component analysis.Anal Chem,2008,80(13):4933-4944.
[6]Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[7]Raamsdonk LM,Teusink B,Broadhurst D,Zhang N,Hayes A,Walsh MC,Berden JA,Brindle KM,Kell DB,Rowland JJ,Westerhoff HV,van Dam K,Oliver SG.A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations.Nat Biotechnol,2001,19(1):45-50.
[8]Nicholson JK,Connelly J,Lindon.JC,Holmes Holmes E.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[9]倪宗瓒.医学统计学[M].第一版,北京:高等教育出版社,2004,127-129.
[10]胡良平.口腔医学科研设计与统计分析[M].第一版,北京:人民军医出版社,2007,227-231.
[11]Ramadan Z,Jacobs D,Grigorov M,Kochhar S.Metabolic profiling using principal component analysis,discriminant partial least squares,and genetic algorithms.Talanta,2006,68(5):1683-1691.
[12]Holmes E,Nicholls AW,Lindon JC,Connor SC,Connelly JC,Haselden JN,Damment SJ,Spraul M,Neidig P,Nicholson JK.Chemometric models for toxicity classification based on NMR spectra of biofluids.Chem Res Toxicol,2000,13(6):471-478.
[13]Griffin JL,Williams HJ,Sang E,Clarke K,Rae C,Nicholson JK.Metabolic profiling of genetic disorders:a multitissue(1)H nuclear magnetic resonance spectroscopic and pattern recognition study into dystrophic tissue.Anal Biochem,2001,293(1):16-21.
[14]Brindle JT,Antti H,Holmes E,Tranter G,Nicholson JK,Bethell HW,Clarke S,Schofield PM,McKilligin E,Mosedale DE,Grainger DJ.Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.Nat Med,2002,8(12):1439-1444.
[15]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[16]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[17]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[18]Gavaghan CL,Holmes E,Lenz E,Wilson ID,Nicholson JK.An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences:application to the C57BL10J and Alpk:ApfCD mouse.FEBS Lett,2000,484(3):169-174.
[19]Waterfield CJ,Turton JA,Scales MD,Timbrell JA.Investigations into the effects of various hepatotoxic compounds on urinary and liver taurine levels in rats.Arch Toxicol,1993,67(4):244-254.
[20]Griffin JL,Troke J,Walker LA,Shore RF,Lindon JC,Nicholson JK.The biochemical profile of rat testicular tissue as measured by magic angle spinning 1H NMR spectroscopy.FEBS Lett,2000,486(3):225-229.
[21]Diehl KH,Hull R,Morton D,Pfister R,Rabemampianina Y,Smith D,Vidal JM,van de Vorstenbosch C.A good practice guide to the administration of substances and removal of blood,including routes and volumes.J Appl Toxicol,2001,21(1):15-23.
[22]Nicholls AW,Holmes E,Lindon JC,Shockcor JP,Farrant RD,Haselden JN,Damment SJ,Waterfield CJ,Nicholson JK.Metabonomic investigations into hydrazine toxicity in the rat.Chem Res Toxicol,2001,14(8):975-987.
[23]Robosky LC,Robertson DG,Baker JD,Rane S,Reily MD.In vivo toxicity screening programs using metabonomics.Comb Chem High Throughput Screen,2002,5(8):651-662.
[24]Wang Y,Bollard ME,Keun H,Antti H,Beckonert O,Ebbels TM,Lindon JC,Holmes E,Tang H,Nicholson JK.Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning 1H nuclear magnetic resonance spectroscopy of liver tissues.Anal Biochem,2003,323(1):26-32.
[25]Rantalainen M,Cloarec O,Beckonert O,Wilson ID,Jackson D,Tonge R,Rowlinson R,Rayner S,Nickson J,Wilkinson RW,Mills JD,Trygg J,Nicholson JK,Holmes E.Statistically integrated metabonomic-proteomic studies on a human prostate cancer xenograft model in mice.J Proteome Res,2006,5(10):2642-2655.
[26]Robertson DG;Reily MD,Sigler RE,Wells DF,Paterson DA,Braden TK.Metabonomics:evaluation of nuclear magnetic resonance(NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants.Toxicol Sci,2000,57(2):326-337.
[27]Waters NJ,Waterfield CJ,Farrant RD,Holmes E,Nicholson JK.Integrated metabonomic analysis of bromobenzene-induced hepatotoxicity:novel induction of 5-oxoprolinosis.J Proteome Res,2006,5(6):1448-1459.
[28]Beckonert O,Keun HC,Ebbels TM,Bundy J,Holmes E,Lindon JC,Nicholson JK.Metabolic profiling,metabolomic and metabonomic procedures for NMR spectroscopy of urine,plasma,serum and tissue extracts.Nat Protoc,2007,2(11):2692-2703.
[29]Coen M,Hong YS,Clayton TA,Rohde CM,Pearce JT,Reily MD,Robertson DG,Holmes E,Lindon JC,Nicholson JK.The mechanism of galactosamine toxicity revisited;a metabonomic study.J Proteome Res,2007,6(7):2711-2719.
[30]Lindon JC,Holmes E,Nicholson JK.Metabonomics in pharmaceutical R&D.FEBS J,2007,274(5):1140-1151.
[31]Teague CR,Dhabhar FS,Barton RH,Beckwith-Hall B,Powell J,Cobain M,Singer B,McEwen BS,Lindon JC,Nicholson JK,Holmes E.Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats.J Proteome Res,2007,6(6):2080-2093.
[1]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[2]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[3]Lowry OH,Rosebrough NJ,Farr AL,Randall RJ.Protein measurement with the folin phenol reagent.J Biol Chem 1951;193(1):265-275.
[4]Ohkawa H,Ohishi N,Yagi K.Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.Anal Biochem 1979;95(2):351-358.
[5]Moron MS,Depierre JW,Mannervik B.Levels of glutathione,glutathione reductase and glutathione S-transferase activities in rat lung and liver.Biochim Biophys Acta,1979,582(1):67-78.
[6]Gartland KP,Beddell CR,Lindon JC,Nicholson JK.Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine.Mol Pharmacol,1991,39(5):629-642.
[7]Holmes E,Nicholls AW,Lindon JC,Ramos S,Spraul M,Neidig P,Connor SC,Connelly J,Damment SJ,Haselden J,Nicholson JK.Development of a model for classification of toxin-induced lesions using 1H NMR spectroscopy of urine combined with pattern recognition.NMR Biomed,1998,11(4-5):235-244.
[8]Nicholls AW,Holmes E,Lindon JC,Shockcor JP,Farrant RD,Haselden JN,Damment SJ,Waterfield CJ,Nicholson JK.Metabonomic investigations into hydrazine toxicity in the rat.Chem Res Toxicol,2001,14(8):975-987.
[9]Azmi J,Griffin JL,Antti H,Shore RF,Johansson E,Nicholson JK,Holmes E.Metabolic trajectory characterisation of xenobiotic-induced hepatotoxic lesions using statistical batch processing of NMR data.Analyst,2002,127(2):271-276.
[10]Keun HC,Ebbels TM,Bollard ME,Beckonert O,Antti H,Holmes E,Lindon JC,Nicholson JK.Geometric trajectory analysis of metabolic responses to toxicity can define treatment specific profiles.Chem Res Toxicol,2004,17(5):579-587.
[11]Siculella L,Sabetta S,di Summa R,Leo M,Giudetti AM,Palmieri F,Gnoni GV.Starvation-induced posttranscriptional control of rat liver mitochondrial citrate carrier expression.Biochem Biophys Res Commun,2002,299(3):418-423.
[12]Connor SC,Wu W,Sweatman BC,Manini J,Haselden JN,Crowther DJ,Waterfield CJ.Effects of feeding and body weight loss on the 1H-NMR-based urine metabolic profiles of male Wistar Han rats:implications for biomarker discovery.Biomarkers,2004,9(2):156-179.
[13]Foxall PJ,Bending MR,Gartland KP,Nicholson JK.Acute renal failure following accidental cutaneous absorption of phenol:application of NMR urinalysis to monitor the disease process.Hum Toxicol,1989,8(6):491-496.
[14]Buckalew Jr VM.Nephrolithiasis in renal tubular acidosis.J Urol,1989,141(3 Pt 2):731-737.
[15]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[16]Galvani M,Ferrini D,Puggioni R,Ruggeri S,Ottani F.New markers for early diagnosis of acute myocardial infarction.Int J Cardiol,1998,65(Suppl 1):S17-22.
[17]Griffin JL,Troke J,Walker LA,Shore RF,Lindon JC,Nicholson JK.The biochemical profile of rat testicular tissue as measured by magic angle spinning 1H NMR spectroscopy.FEBS Lett,2000,486(3):225-229.
[18]Sharp RR,Barrett JC.The environmental genome project:ethical,legal,and social implications.Environ Health Perspect,2000,108(4):279-281.
[19]Gatley SJ,Sherratt HS.The synthesis of hippurate from benzoate and glycine by rat liver mitochondria.Submitochondrial localization and kinetics.Biochem J,1977,166(1):39-47.
[20]Enan E,Lasley B,Stewart D,Overstreet J,Vandevoort CA.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity.Reprod Toxicol,1996,10(3):191-198.
[21]Williams RE,Jacobsen M,Lock EA.1H NMR pattern recognition and 31P NMR studies with d-Serine in rat urine and kidney,time-and dose-related metabolic effects.Chem Res Toxicol,2003,16(10):1207-1216.
[22]Lenz EM,Bright J,Knight R,Wilson ID,Major H.A metabonomic investigation of the biochemical effects of mercuric chloride in the rat using 1H NMR and HPLC-TOF/MS:time dependent changes in the urinary profile of endogenous metabolites as a result of nephrotoxicity.Analyst,2004,129(6):535-541.
[23]Lenz EM,Bright J,Knight R,Westwood FR,Davies D,Major H,Wilson ID.Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat.Biomarkers,2005,10(2-3): 173-187.
[24]Holmes E,Bonner FW,Nicholson JK.Comparative studies on the nephrotoxicity of 2-bromoethanamine hydrobromide in the Fischer 344 rat and the multimammate desert mouse(Mastomys natalensis).Arch Toxicol,1995,70(2):89-95.
[25]Williams RE,Cottrell L,Jacobsen M,Bandara LR,Kelly MD,Kennedy S,Lock EA.1H-Nuclear magnetic resonance pattern recognition studies with N-phenylanthranilic acid in the rat:time- and dose-related metabolic effects.Biomarkers,2003,8(6):472-490.
[26]Li XJ,Feng JH,Zhang SR,Pei FK,Chen X,Nie YX.Effect of rare earth element on the metabolism in rats by high resolution proton nuclear magnetic resonance spectroscopy.Chinese J Anal Chem,2000,28(12):1472-1475.
[27]Sanins SM,Nicholson JK,Elcombe C,Timbrell JA.Hepatotoxin-induced hypertaurinuria:a proton NMR study.Arch Toxicol,1990,64(5):407-411.
[28]Waterfield CJ,Turton JA,Scales MD,Timbrell JA.Investigations into the effects of various hepatotoxic compounds on urinary and liver taurine levels in rats.Arch Toxicol,1993,67(4):244-254.
[29]Nicholson JK,Connelly J,Lindon JC,Holmes Holmes E.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[1]Moennikes O,Loeppen S,Buchmann A,Andersson P,Ittrich C,Poellinger L,Schwarz MA.Constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice.Cancer Res,2004,64(14):4707-4710.
[2]Baba T,Mimura J,Nakamura N,Harada N,Yamamoto M,Morohashi K,Fujii-Kuriyama Y.Intrinsic function of the aryl hydrocarbon(dioxin) receptor as a key factor in female reproduction.Mol Cell Biol,2005,25(22):10040-10051.
[3]Pollenz RS.The mechanism of AH receptor protein down-regulation(degradation) and its impact on AH receptor-mediated gene regulation.Chem Biol Interact,2002,141(1-2):41-61.
[4]Andersson P,Ridderstad A,McGuire J,Pettersson S,Poellinger L,Hanberg A.A constitutively active aryl hydrocarbon receptor causes loss of peritoneal B1 cells.Biochem Biophys Res Commun,2003,302(2):336-341.
[5]Boutros PC,Moffat ID,Franc MA,Tijet N,Tuomisto J,Pohjanvirta R,Okey AB.Dioxin-responsive AHRE-Ⅱ gene battery:identification by phylogenetic footprinting.Biochem Biophys Res Commun,2004,321(3):707-715.
[6]Nebert DW,Dalton TP,Okey AB,Gonzalez FJ.Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.J Biol Chem,2004,279(23):23847-23850.
[7]Nebert DW,Roe AL,Dieter MZ,Solis WA,Yang Y,Dalton TP.Role of the aromatic hydrocarbon receptor and[Ah]gene battery in the oxidative stress response,cell cycle control,and apoptosis.Biochem Pharmacol,2000,59(1):65-85.
[8]Mimura J,Fujii-Kuriyama Y.Functional role of AhR in the expression of toxic effects by TCDD.Biochim Biophys Acta,2003,1619(3):263-268.
[9]Fujii-Kuriyama Y,Mimura J.Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes.Biochem Biophys Res Commun,2005,338(1):311-317.
[10]Knerr S,Schaefer J,Both S,Mally A,Dekant W,Schrenk D.2,3,7,8-tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells.Mol Nutr Food Res,2006,50(4-5):378-384.
[11]Hu W,Sorrentino C,Denison MS,Kolaja K,Fielden MR.Induction of cypl al is a nonspecific biomarker of aryl hydrocarbon receptor activation:results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro.Mol Pharmacol,2007,71(6):1475-1486.
[12]Chubb LS,Andersen ME,Broccardo CJ,Legare ME,Billings RE,Dean CE,Hanneman WH.Regional induction of CYP 1A1 in rat liver following treatment with mixtures of PCB 126 and PCB 153.Toxicol Pathol,2004,32(4):467-473.
[13]Leung YK,Lau KM,Mobley J,Jiang Z,Ho SM.Overexpression of cytochrome P450 1A1 and its novel spliced variant in ovarian cancer cells:alternative subcellular enzyme compartmentation may contribute to carcinogenesis.Cancer Res,2005,65:3726-3734.
[14]Gauger KJ,Giera S,Sharlin DS,Bansal R,Iannacone E,Zoeller RT.Polychlorinated biphenyls 105 and 118 form thyroid hormone receptor agonists after cytochrome P4501A1 activation in rat pituitary GH3 cells.Environ Health Perspect,2007,115(11):1623-1630.
[15]Lin PH,Lin CH,Huang CC,Chuang MC,Lin P.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) induces oxidative stress,DNA strand breaks,and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines.Toxicol Lett,2007,172(3):146-158.
[16]Sridevi N,Venkataraman P,Senthilkumar K,Krishnamoorthy G,Arunakaran J.Oxidative stress modulates membrane bound ATPases in brain regions of PCB(Aroclor1254) exposed rats:Protective role of alpha-tocopherol.Biomed Pharmacother,2007,61(7):435-440.
[17]Chen ZH,Hurh YJ,Na HK,Kim JH,Chun YJ,Kim DH,Kang KS,Cho MH,Surh YJ.Resveratrol inhibits TCDD-induced expression of CYP 1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells.Carcinogenesis,2004,25(10):2005-2013.
[18]Marlowe JL,Puga A.Aryl hydrocarbon receptor,cell cycle regulation,toxicity,and tumorigenesis.J Cell Biochem,2005,96(6):1174-1184.
[19]Tijet N,Boutros PC,Moffat ID,Okey AB,Tuomisto J,Pohjanvirta R.Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries.Mol Pharmacol,2006,69(1):140-153.
[20]Xu L,Li AP,Kaminski DL,Ruh MF.2,3,7,8 Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes.Chem Biol Interact,2000,124(3):173-189.
[21]Henry TR,Nesbit DJ,Heideman W,Peterson RE.Relative potencies of polychlorinated dibenzo-p-dioxin,dibenzofuran,and biphenyl congeners to induce cytochrorne P4501A mRNA in a zebrafish liver cell line.Environ Toxicol Chem,2001,20(5):1053-1058.
[22]Kono Y,Okada S,Tazawa Y,Kanzaki S,Mura T;Ueta E,Nanba E,Otsuka Y.Effect of lactational exposure to 1,2,3,4-tetrachlorodibenzo-p-dioxin on cytochrome P-450 1A1 mRNA in the neonatal rat liver: quantitative analysis by the competitive RT-PCR method.Pediatr Int,2001,43(5):458-464.
[23]Twaroski TP,O'Brien ML,Larmonier N,Glauert HP,Robertson LW.Polychlorinated biphenyl-induced effects on metabolic enzymes,AP-1 binding,vitamin E,and oxidative stress in the rat liver.Toxicol Appl Pharmacol,2001,171(2):85-93.
[24]Hassoun EA,Wang H,Abushaban A,Stohs SJ.Induction of oxidative stress in the tissues of rats after chronic exposure to TCDD,2,3,4,7,8-pentachlorodibenzofuran,and 3,3',4,4',5-pentachlorobiphenyl.J Toxicol Environ Health A,2002,65(12):825-842.
[25]Kern PA,Fishman RB,Song W,Brown AD,Fonseca V.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on oxidative enzymes in adipocytes and liver.Toxicology,2002,171(2-3):117-125.
[26]Latchoumycandane C,Chitra KC,Mathur PP.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antioxidant system in mitochondrial and microsomal fractions of rat testis.Toxicology,2002,171(2-3):127-135.
[27]Murugesan P,Senthilkumar J,Balasubramanian K,Aruldhas MM,Arunakaran J.Impact of polychlorinated biphenyl Aroclor1254 on testicular antioxidant system in adult rats.Hum Exp Toxicol,2005,24(2):61-66.
[28]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini DN,Kanagaraj P,Stanley AJ,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclorl254) induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[29]Venkataraman P,Muthuvel R,Krishnamoorthy G,Arunkumar A,Sridhar M,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.PCB(Aroclor1254) enhances oxidative damage in rat brain regions:Protective role of ascorbic acid.Neurotoxicology,2007,28(3):490-498.
[30]Aas E,Baussant T,Balk L,Liewenborg B,Andersen OK.PAH metabolites in bile,cytochrome P4501A and DNA adducts as environmental risk parameters for chronic oil exposure:a laboratory experiment with Atlantic cod.Aquat Toxicol,2000,51(2):241-258.
[31]Kostka G.The use of biomarkers in the assessment of health risk from environmental exposure to chemical carcinogens.Rocz Panstw Zakl Hig,2003,54(S1):30-31.
[32]Borras M,Nadal J.Biomarkers of genotoxicity and other end-points in an integrated approach to environmental risk assessment.Mutagenesis,2004,19:165-168.
[33]Cossu C,Doyotte A,Babut M,Exinger A,Vasseur P.Antioxidant biomarkers in freshwater bivalves,Unio tumidus,in response to different contamination profiles of aquatic sediments.Ecotoxicol Environ Saf,2000, 45(2):106-121.
[34]den Besten PJ,Valk S,van Weerlee E,Nolting RF,Postma JF,Everaarts JM.Bioaccumulation and biomarkers in the sea star Asterias rubens(Echinodermata:Asteroidea):a North Sea field study.Mar Environ Res,2001,51(4):365-387.
[35]Pascual P,Pedrajas JR,Toribio F,Lopez-Barea J,Peinado J.Effect of food deprivation on oxidative stress biomarkers in fish(Spams aurata).Chem Biol Interact,2003,145(2):191-199.
[36]Cheung CC,Siu WH,Richardson BJ,De Luca-Abbott SB,Lam PK.Antioxidant responses to benzo[a]pyrene and Aroclor 1254 exposure in the green-lipped mussel,Perna viridis.Environ Pollut,2004,128(3):393-403.
[37]Cheung CC,Zheng GJ,Lam PK,Richardson BJ.Relationships between tissue concentrations of chlorinated hydrocarbons(polychlorinated biphenyls and chlorinated pesticides) and antioxidative responses of marine mussels,Perna viridis.Mar Pollut Bull,2002,45(1-12):181-191.
[38]Oruc EO,Sevgiler Y,Uner N.Tissue-specific oxidative stress responses in fish exposed to 2,4-D and azinphosmethyl.Comp Biochem Physiol C Toxicol Pharmacol,2004,137(1):43-51.
[39]Verweij F,Booij K,Satumalay K,van der Molen N,van der Oost R.Assessment of bioavailable PAH,PCB and OCP concentrations in water,using semipermeable membrane devices(SPMDs),sediments and caged carp.Chemosphere,2004,54(11):1675-1689.
[40]Kammenga JE,Arts MSJ,Oude-Breuil WJM.HSP60 as a potential biomarker of toxic stress in the nematode plectus acuminatus.Arch Environ Contam Toxicol,1998,34(3):253-258.
[41]Pirillo A,Norata GD,Zanelli T,Catapano AL.Overexpression of Inducible Heat Shock Protein 70 in COS-1 Cells Fails to Protect From Cytotoxicity of Oxidized LDLs.Arterioscler Thromb Vasc Biol,2001,21(3):348-354.
[42]Miyabara EH,Martin JL,Griffin TM,Moriscot AS,Mestril R.Overexpression of inducible 70-kDa heat shock protein in mouse attenuates skeletal muscle damage induced by cryolesioning.Am J Physiol Cell Physiol,2006,290(4):C1128-C1138.
[43]Chu I,Lecavalier P,Hakansson H,Yagminas A,Valli VE,Poon P,Feeley M.Mixture effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls congeners in rats.Chemosphere,2001,43(4-7):807-814.
[44]Wade MG,Foster WG,Younglai EV,McMahon A,Leingartner K,Yagminas A,Blakey D,Fournier M,Desaulniers D,Hughes CL.Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats:systemic,immune,and reproductive effects.Toxicol Sci,2002,67(1):131-143.
[45]Desaulniers D,Leingartner K,Musicki B,Yagminas A,Xiao GH,Cole J,Marro L,Charbonneau M,Tsang BK.Effects of postnatal exposure to mixtures of non-ortho-PCBs,PCDDs,and PCDFs in prepubertal female rats.Toxicol Sci,2003,75(2):468-480.
[46]Crofton KM,Craft ES,Hedge JM,Gennings C,Simmons JE,Carchman RA,Carter Jr WH,DeVito MJ.Thyroid-hormone-disrupting chemicals:evidence for dose-dependent additivity or synergism.Environ Health Perspect,2005,113(11):1549-1554.
[47]van Birgelen AP,Fase KM,van der Kolk J,Poiger H,Brouwer A,Seinen W,van den Berg M.Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.Environ Health Perspect,1996,104(5):550-557.
[48]Sugatani J,Kojima H,Ueda A,Kakizaki S,Yoshinari K,Gong QH,Owens IS,Negishi M,Sueyoshi T.The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1gene and regulation by the nuclear receptor CAR.Hepatology,2001,33(5):1232-1238.
[49]Craft ES,DeVito MJ,Crofton KM.Comparative responsiveness of hypothyroxinemia and hepatic enzyme induction in long-evans rats versus C57BL/6J mice exposed to TCDD-like and phenobarbital-like polychlorinated biphenyl congeners.Toxicol Sci,2002,68(2):372-380.
[50]Tabb MM,Kholodovych V,Grun F,Zhou C,Welsh WJ,Blumberg B.Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor(SXR).Environ Health Perspect,2004,112(2):163-169.
[51]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[52]Chen G,Bunce NJ.Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathway.Environ Toxicol,2004,19(5):480-489.
[53]Snh J,Kang JS,Yang KH,Kaminski NE.Antagonism of aryl hydrocarbon receptor-dependent induction of CYP1A1 and inhibition of IgM expression by di-ortbo-substituted polychlorinated biphenyls.Toxicol Appl Pharmacol,2003,187(1):11-21.
[54]Petrulis JR,Bunce NJ.Competitive behavior in the interactive toxicology of halogenated aromatic compounds.J Biochem Mol Toxicol,2000,14(2):73-81.
[55]Groten JP.Mixtures and interactions.Food Chem Toxicol,2000,38(1 Suppl):S65-71.
[2]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[3]Friedmann AS.Atrazine inhibition of testosterone production in rat males following peripubertal exposure.Reprod Toxicol,2002,16(3):275-279.
[4]Iwasaki T,Miyazaki W,Takeshita A,Kuroda Y,Koibuchi N.Polychlorinated biphenyls suppress thyroid hormone-induced transactivation.Biochem Biophys Res Commun,2002,299(3):384-388.
[5]Gunnarsson D,Nordberg G,Lundgren P,Selstam G.Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats.Toxicology,2003,183(1-3):57-63.
[6]Hsu PC,Li MH,Guo YL.Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats.Toxicology,2003,187(2-3):117-126.
[7]Suzuki T,Mizuo K,Nakazawa H,Funae Y,Fushiki S,Fukushima S,Shirai T,Narita M.Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice:enhancement of the methamphetamine-induced abuse state.Neuroscience,2003,117(3):639-644.
[8]Greim HA.The Endocrine and Reproductive System:Adverse Effects of Hormonally Active Substances?Pediatrics,2004,113(4):1070-1075.
[9]Karcher W.Recent trends and developments in the EU in the environmental control and management of chemicals.Ecotoxicol Environ Saf,1998,40(1-2):97-102.
[10]Kavlock RJ.Overview of endocrine disruptor research activity in the United States.Chemosphere,1999,39(8):1227-1236.
[11]Reiter LW,DeRosa C,Kavlock RJ,Lucier G,Mac MJ,Melillo J,Melnick RL,Sinks T,Walton BT.The U.S.federal framework for research on endocrine disruptors and an analysis of research programs supported during fiscal year 1996.Environ Health Perspect,1998,106(3):105-113.
[12]Shelby MD,Newbold RR,Tully DB,Chae K,Davis VL.Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays.Environ Health Perspect,1996,104(12):1296-1300.
[13]Gray Jr LE,Kelce WR,Wiese T,Tyl R,Gaido K,Cook J,Klinefelter G,Desaulniers D,Wilson E,Zacharewski T,Waller C,Foster P,Laskey J,Reel J,Giesy J,Laws S,McLachlan J,Breslin W,Cooper R,Di Giulio R,Johnson R,Purdy R,Mihaich E,Safe S,Colborn T.Endocrine Screening Methods Workshop report:detection of estrogenic and androgenic hormonal and antihormonal activity for chemicals that act via receptor or steroidogenic enzyme mechanisms.Reprod Toxicol,1997,11(5):719-750.
[14]Nishikawa J,Saito K,Goto J,Dakeyama F,Matsuo M,Nishihara T.New screening methods for chemicals with hormonal activities using interaction of nuclear hormone receptor with coactivator.Toxicol Appl Pharmacol,1999,154(1):76-83.
[15]Coen M,Hong YS,Clayton TA,Rohde CM,Pearce JT,Reily MD,Robertson DG,Holmes E,Lindon JC,Nicholson JK.The mechanism of galactosamine toxicity revisited;a metabonomic study.J Proteome Res,2007,6(7):2711-2719.
[16]Lindon JC,Holmes E,Nicholson JK.Metabonomics in pharmaceutical R&D.FEBS J,2007,274(5):1140-1151.
[17]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[18]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[19]Lindon JC,Nicholson JK,Holmes E,Antti H,Bollard ME,Keun H,Beckonert O,Ebbels TM,Reily MD,Robertson D,Stevens GJ,Luke P,Breau AP,Cantor GH,Bible RH,Niederhauser U,Senn,H Schlotterbeck G,Sidelmann UG,Laursen SM,Tymiak A,Car BD,Lehman-McKeeman L,Colet JM,Loukaci A,Thomas C.Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.Toxicol Appl Pharmacol,2003,187(3):137-146.
[20]Nicholson JK,Lindon JC,Holmes E.‘Metabonomics’:understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[21]Nicholson JK,Connelly J,Lindon JC,Holmes.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[22]Aas E,Baussant T,Balk L,Liewenborg B,Andersen OK.PAH metabolites in bile,cytochrome P4501A and DNA adducts as environmental risk parameters for chronic oil exposure:a laboratory experiment with Atlantic cod.Aquat Toxicol,2000,51(2):241-258.
[23]Kostka G.The use of biomarkers in the assessment of health risk from environmental exposure to chemical carcinogens.Rocz Panstw Zakl Hig,2003,54(S1):30-31.
[24]Borras M,Nadal J.Biomarkers of genotoxicity and other end-points in an integrated approach to environmental risk assessment.Mutagenesis,2004,19:165-168.
[25]Poland A,Knutson JC.2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons:examination of the mechanism of toxicity.Annu Rev Pharmacol Toxicol,1982,22:517-554.
[26]Viel J F,Arveux P,Baverel J,Cahn J Y.Soft-tissue sarcoma and non-hodgkin's lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels.Am J Epidemiol,2000,152(1):13-19.
[27]Domingo JL,Agramunt MC,Nadal M,Schuhmacher M,Corbella J.Health risk assessment of PCDD/PCDF exposure for the population living in the vicinity of a municipal waste incinerator.Arch Environ Contam Toxicol,2002,43(4):461-465.
[29]Cole P,Trichopoulos D,Pastides H,Starr T,Mandel JS.Dioxin and cancer:a critical review.Regul Toxicol Pharmacol,2003,38(3):378-388.
[29]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[30]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[31]Safe SH.Polychlorinated biphenyls(PCBs):environmental impact,biochemical and toxic responses,and implications for risk assessment.Crit Rev Toxicol,1994,24(2):87-149.
[32]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini D N,Kanagaraj P,Stanley A J,Srinivasan N,Balasubramanian K,Aruldhas M M,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclor 1254) induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[33]Nagayama J,Tsuji H,Iida T,Nakagawa R,Matsueda T,Hirakawa H,Yanagawa T,Fukushige J,Watanabe T.Immunologic effects of perinatal exposure to dioxins,PCBs and organochlorine pesticides in Japanese infants.Chemosphere,2007;67(9):S393-398.
[1]Baker VA.Endocrine disrupters--testing strategies to assess human hazard.Toxicol In Vitro,2001,15(4-5):413-419.
[2]Larsen JC.Risk assessments of polychlorinated dibenzo-p-dioxins,polychlorinated dibenzofurans,and dioxin-like polychlorinated biphenyls in food.Mol Nutr Food Res,2006,50(10):885-896.
[3]Dahl P,Lindstrom G,Wiberg K,Rappe C.Absorption of polychlorinated biphenyls,dibenzo-p-dioxins and dibenzofurans by breast-fed infants.Chemosphere,1995,30(12):2297-2306.
[4]Leung HW,Wendling JM,Orth R,Hileman F,Paustenbach DJ.Relative distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatic and adipose tissues.Toxicol Lett,1990,50(2-3):275-282.
[5]Pohjanvirta R,Vartiainen T,Uusi-Rauva A,Monkkonen J,Tuomisto J.Tissue distribution,metabolism,and excretion of 14C-TCDD in a TCDD-susceptible and a TCDD-resistant rat strain.Pharmacol Toxicol,1990,66(2):93-100.
[6]Kreuzer PE,Csanady GA,Baur C,Kessler W,Papke O,Greim H,Filser JG.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) and congeners in infants.A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.Arch Toxicol,1997,71(6):383-400.
[7]Clewell HJ,Robinan Gentry P,Covington TR,Sarangapani R,Teeguarden JG Evaluation of the potential impact of age-and gender-specific pharmacokinetic differences on tissue dosimetry.Toxicol Sci,2004,79(2):381-393.
[8]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[9]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[10]Tuomisto JT,Pohjanvirta R,Unkila M,Tuomisto J.TCDD-induced anorexia and wasting syndrome in rats:effects of diet-induced obesity and nutrition.Pharmacol Biochem Behav,1999,62(4):735-742.
[11]Coenraads PJ,Olie K,Tang NJ.Blood lipid concentrations of dioxins and dibenzofurans causing chloracne.Br J Dermatol,1999,141(4):694-697.
[12]Neuberger M,Kundi M,Jager R.Chloracne and morbidity after dioxin exposure(preliminary results). Toxicol Lett,1998,96-97:347-350.
[13]Sweeney MH,Mocarelli P.Human health effects after exposure to 2,3,7,8-TCDD.Food Addit Contam,2000,17(4):303-316.
[14]Connell BJ,Singh A,Chu I.Interaction of PCB congeners and 2,3,7,8-TCDD in the rat liver:an electron microscope study.J Submicrosc Cytol Pathol,1998,30(1):157-163.
[15]Walter GL,Jones PD,Giesy JP.Pathologic alterations in adult rainbow trout,oncorhynchus mykiss,exposed to dietary 2,3,7,8-tetrachlorodibenzo-p-dioxin.Aquat Toxicol,2000,50(4):287-299.
[16]刘云儒,汤乃军,任大林.2,3,7,8-四氯二苯-p-二恶英对大鼠肝脏芳香烃受体和细胞色素p4501A1mRNA的诱导.中华劳动卫生职业病杂志,2003,21(6):417-419.
[17]汤乃军,刘云儒,任大林.2,3,7,8-四氯二苯并二恶英对SD大鼠肝脏SOD、GST、MDA影响的实验研究.中国工业医学杂志,2003,16(6):335-337.
[18]Kern PA,Fishman RB,Son g W,Brown AD,Fonseca V.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on oxidative enzymes in adipocytes and liver.Toxicology,2002,171(2-3):117-125.
[19]Gannon M,Gilday D,Rifkind AB.TCDD induces CYP1A4 and CYP1A5 in chick liver and kidney and only CYP1A4,an enzyme lacking arachidonic acid epoxygenase activity,in myocardium and vascular endothelium.Toxicol Appl Pharmacol,2000,164(1):24-37.
[20]Fletcher N,Hanberg A,H(?)kansson H.Hepatic vitamin a depletion is a sensitive marker of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) exposure in four rodent species.Toxicol Sci,2001,62(1):166-175.
[21]Narasimhan TR,Craig A,Arellano L,Harper N,Howie L,Menache M,Birnbaum L,Safe S.Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cypla-1 and Cypla-2 gene expression and immunotoxicity in female B6C3F1 mice.Fundam Appl Toxicol,1994,23(4):598-607.
[22]Mitchell KA,Paige Lawrence B.Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) renders influenza virus-specific CD8~+ T cells hyporesponsive to antigen.Toxicol Sci,2003,74(1):74-84.
[23]Neff-LaFord HD,Vorderstrasse BA,Lawrence BP.Fewer CTL,not enhanced NK cells,are sufficient for viral clearance from the lungs of immunocompromised mice.Cell Immunol,2003,226(1):54-64.
[24]Camacho IA,Nagarkatti M,Nagarkatti PS.Evidence for induction of apoptosis in T cells from murine fetal thymus following perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD).Toxicol Sci,2004,78(1):96-106.
[25]Egeland GM,Sweeney MH,Fingerhu t MA,Wille KK,Schnorr TM,.Halperin WE.Total serum testosterone and gonadotropins in workers exposed to dioxin.Am J Epidemiol,1994,139(3):272-281.
[26]Li B,Liu HY,Dai LJ,Lu JC,Yang ZM,Huang L.The early embryo loss caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin may be related to the accumulation of this compound in the uterus.Reprod Toxicol,2006,21(3):301-306.
[27]Mably TA,Bjerke DL,Moore RW,Gendron-Fitzpatrick A,Peterson RE.In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin.3.Effects on spermatogenesis and reproductive capability.Toxicol Appl Pharmacol,1992,114(1):118-126.
[28]Latchoumycandane C,Chitra KC,Mathur PP.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) induces oxidative stress in the epididymis and epididymal sperm of adult rats.Arch Toxicol,2003,77(5):280-284.
[29]Brouwer A,Ahlborg UG,Van den Berg M,Birnbaum LS,Boersma ER,Bosveld B,Denison MS,Gray LE,Hagmar L,Holene E.Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants.Eur J Pharmacol,1995,293(1):1-40.
[30]Teraoka H,Dong W,Hiraga T.Zebrafish as a novel experimental model for developmental toxicology.Congenit Anom(Kyoto),2003,43(2):123-132.
[31]Ohsako S,Miyabara Y,Sakaue M,Ishimura R,Kakeyama M,Izumi H,Yonemoto J,Tohyama C.Developmental stage-specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring.Toxicol Sci,2002,66(2):283-292.
[32]Kim SY,Yang JH.Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells.Exp Mol Med,2005,37(1):58-64.
[33]Van Loveren H,Vos J,Putman E,Piersma A.Immunotoxicological consequences of perinatal chemical exposures:a plea for inclusion of immune parameters in reproduction studies.Toxicology,2003,185(3):185-191.
[34]Nyska A,Yoshizawa K,Jokinen MP,Brix AE,Sells DM,Wyde ME,Orzech DP,Kissling GE,Walker NJ.Olfactory epithelial metaplasia and hyperplasia in female harlan sprague-dawley rats following chronic treatment with polychlorinated biphenyls.Toxicol Pathol,2005,33(3):371-377.
[35]Yoshizawa K,Walker NJ,Jokinen MP,Brix AE,Sells DM,Marsh T,Wyde ME,Orzech D,Haseman JK,Nyska A.Gingival carcinogenicity in female harlan sprague-dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.Toxicol Sci,2005,83(1):405-406.
[36]Pavuk M,Michalek JE,Ketchum NS.Prostate cancer in US air force veterans of the Vietnam war.J Expo Sci Environ Epidemiol,2006,16(2):184-190.
[37]Wu Q,Ohsako S,Baba T,Miyamoto K,Tohyama C.Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on preimplantation mouse embryos.Toxicology,2002,174(2):119-129.
[38]Bertazzi PA,Consonni D,Bachetti S,Rubagotti M,Baccarelli A,Zocchetti C,Pesatori AC.Health effects of dioxin exposure:a 20-year mortality study.Am J Epidemiol,2001,153(11):1031-1044.
[39]Poland A,Palen D,Glover E.Tumour promotion by TCDD in skin of HRS/J hairless mice.Nature,1982,300(5889):271-273.
[40]Nyska A,Jokinen MP,Brix AE,Sells DM,Wyde ME,Orzech D,Haseman JK,Flake G,Walker NJ.Exocrine pancreatic pathology in female harlan sprague-dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.Environ Health Perspect,2004,112(8):903-909.
[41]Yoshizawa K,Marsh T,Foley JF,Cai B,Peddada S,Walker NJ,Nyska A.Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female harlan sprague-dawley rats.Toxicol Sci,2005,85(1):594-606.
[42]Signorini S,Gerthoux PM,Dassi C,Cazzaniga M,Brambilla P,Vincoli N,Mocarelli P.Environmental exposure to dioxin:the Seveso experience.Andrologia,2000,32(4-5):263-270.
[43]Jokinen MP,Walker NJ,Brix AE,Sells DM,Haseman JK,Nyska A.Increase in cardiovascular pathology in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,3',4,4',5-pentachlorobiphenyl.Cardiovasc Toxicol,2003,3(4):299-310.
[44]Neuberger M,Rappe C,Bergek S,Cai H,Hansson M,Jager R,Kundi M,Lim CK,Wingfors H,Smith AG.Persistent health effects of dioxin contamination in herbicide production.Environ Res,1999,81(3):206-214.
[45]Baba T,Mimura J,Nakamura N,Harada N,Yamamoto M,Morohashi K,Fujii-Kuriyama Y.Intrinsic function of the aryl hydrocarbon(dioxin) receptor as a key factor in female reproduction.Mol Cell Biol,2005,25(22):10040-10051.
[46]Korkalainen M,Tuomisto J,Pohjanvirta R.Identification of novel splice variants of ARNT and ARNT2 in the rat.Biochem Biophys Res Commun,2003,303(4):1095-1100.
[47]Pongratz I,Mason GG,Poellinger L.Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor.Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity.J Biol Chem,1992,267(19):13728-13734.
[48]Chapman-Smith A,Lutwyche JK,Whitelaw ML.Contribution of the per/arnt/sim(PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators.J Biol Chem,2004,279(7):5353-5362.
[49]Andersson P,Ridderstad A,McGuire J,Pettersson S,Poellinger L,Hanberg A.A constitutively active aryl hydrocarbon receptor causes loss of peritoneal Bl cells.Biochem Biophys Res Commun,2003,302(2):336-341.
[50]Nebert DW,Dalton TP,Okey AB,Gonzalez FJ.Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.J Biol Chem,2004,279(23):23847-23850.
[51]Mimura J,Fujii-Kuriyama Y.Functional role of AhR in the expression of toxic effects by TCDD.Biochim Biophys Acta,2003,1619(3):263-268.
[52]Knerr S,Schaefer J,Both S,Mally A,Dekant W,Schrenk D.2,3,7,8-tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells.Mol Nutr Food Res,2006,50(4-5):378-384.
[53]Backlund M,Ingelman-Sundberg M.Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases.Cell Signal,2005,17(1):39-48.
[54]Enan E,Moran F,VandeVoort CA,Stewart DR,Overstreet JW,Lasley BL.Mechanism of toxic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in cultured human luteinized granulosa cells.Reprod Toxicol,1996,10(6):497-508.
[55]Tan Z,Chang X,Puga A,Xia Y.Activation of mitogen-activated protein kinases(MAPKs) by aromatic hydrocarbons:role in the regulation of aryl hydrocarbon receptor(AHR) function.Biochem Pharmacol,2002,64(5-6):771-780.
[56]Abbott BD,Probst MR.Developmental expression of two members of a new class of transcription factors:Ⅱ.Expression of aryl hydrocarbon receptor nuclear translocator in the C57BL/6N mouse embryo.Dev Dyn,1995,204(2):144-155.
[57]Yu ML,Guo YL,Hsu CC,Rogan WJ.Menstruation and reproduction in women with polychlorinated biphenyl(PCB) poisoning:long-term follow-up interviews of the women from the Taiwan Yucheng cohort.Int J Epidemiol,2000,29(4):672-677.
[58]Bernard A,Hermans C,Broeckaert F,De Poorter G,De Cock A,Houins G.Food contamination by PCBs and dioxins.Nature,1999,401(6750):231-232.
[59]Litten S,Fowler B,Luszniak D.Identification of a novel PCB source through analysis of 209 PCB congeners by US EPA modified method 1668.Chemosphere,2002,46(9-10):1457-1459.
[60]Sandau CD,Ayotte P,Dewailly E,Duffe J,Norstrom RJ.Pentachlorophenol and hydroxylated polychlorinated biphenyl metabolites in umbilical cord plasma of neonates from coastal populations in Quebec.Environ Health Perspect,2002,110(4):411-417.
[61]Soechitram SD,Athanasiadou M,Hovander L,Bergman A,Sauer PJ.Fetal exposure to PCBs and their hydroxylated metabolites in a Dutch cohort.Environ Health Perspect,2004,112(11):1208-1212.
[62]Carlsen E,Giwercman A,Keiding N,Skakkebaek NE.Evidence for decreasing quality of semen during past 50 years.BMJ,1992,305(6854):609-613.
[63]Wolff MS.Occupational exposure to polychlorinated biphenyls(PCBs).Environ Health Perspect,1985,60:133-138.
[64]Haraguchi K,Hirose Y,Masuda Y,Kato Y,Kimura R.Metabolism of 3,3',4,4',5-penta-and 2,2',3,3',4,4'-hexachlorobiphenyls in rats.Fukuoka Igaku Zasshi,1999,90(5):210-219.
[65]Ross G.The public health implications of polychlorinated biphenyls(PCBs) in the environment.Ecotoxicol Environ Saf,2004,59(3):275-291.
[66]Krishnamoorthy G,Murugesan P,Muthuvel R,Gunadharini DN,Vijayababu MR,Arunkumar A,Venkataraman P,Aruldhas MM,Arunakaran J.Effect of Aroclor1254 on Sertoli cellular antioxidant system,androgen binding protein and lactate in adult rat in vitro.Toxicology,2005,212(2-3):195-205.
[67]Murugesan P,Muthusamy T,Balasubramanian K,Arunakaran J.Studies on the protective role of vitamin C and E against polychlorinated biphenyl(Aroclor1254)--induced oxidative damage in Leydig cells.Free Radic Res,2005 a,39(11):1259-1272.
[68]Murugesan P,Senthilkumar J,Balasubramanian K,Aruldhas MM,Arunakaran J.Impact of polychlorinated biphenyl Aroclor1254 on testicular antioxidant system in adult rats.Human and Experimental Toxicology,2005 b,24:61-66.
[69]Murugesan P,Balaganesh M,Balasubramanian K,Arunakaran J.Effects of polychlorinated biphenyl(Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells.J Endocrinol,2007,192(2):325-338.
[70]Murugesan P,Muthusamy T,Balasubramanian K,Arunakaran J.Polychlorinated biphenyl(Aroclor 1254) inhibits testosterone biosynthesis and antioxidant enzymes in cultured rat Leydig cells.Reprod Toxicol,2008,25(4):447-454.
[71]Hertz-Picciotto I,Charles MJ,James RA,Keller JA,Willman E,Teplin S.In utero polychlorinated biphenyl exposures in relation to fetal and early childhood growth.Epidemiology,2005,16(5):648-656.
[72]Knerr S,Schrenk D.Carcinogenicity of“non-dioxinlike”polychlorinated biphenyls.Crit Rev Toxicol, 2006,36(9):663-694.
[73]Guo YL,Yu ML,Hsu CC,Rogan WJ.Chloracne,goiter,arthritis,and anemia after polychlorinated biphenyl poisoning:14-year follow-Up of the Taiwan Yucheng cohort.Environ Health Perspect,1999,107(9):715-719.
[74]Kimbrough RD,Krouskas C.Polychlorinated biphenyls,TEQs,children,and data analysis.Vet Hum Toxicol,2002,44(6):354-357.
[75]Kimbrough RD,Krouskas CA.Human exposure to polychlorinated biphenyls and health effects:a critical synopsis.Toxicol Rev,2003,22(4):217-233.
[76]Kimbrough RD,Doemland ML,LeVois ME.Mortality in male and female capacitor workers exposed to polychlorinated biphenyls.J Occup Environ Med,1999,41(3):161-171.
[77]Kimbrough RD,Doemland ML,Krouskas CA.Analysis of research studying the effects of polychlorinated biphenyls and related chemicals on neurobehavioral development in children.Vet Hum Toxicol,2001,43(4):220-228.
[78]Kilic N,Sandal S,Colakoglu N,Kutlu S,Seyran A,Yilmaz B.Endocrine disruptive effects of polychlorinated biphenyls on the thyroid gland in female rats.Tohoku J Exp Med,2005,206(4):327-332.
[79]Khan MA,Hansen LG Ortho-substituted polychlorinated biphenyl(PCB) congeners(95 or 101) decrease pituitary response to thyrotropin releasing hormone.Toxicol Lett,2003,144(2):173-182.
[80]Hsu PC,Huang W,Yao WJ,Wu MH,Guo YL,Lambert GH.Sperm changes in men exposed to polychlorinated biphenyls and dibenzofurans.JAMA,2003 a,289(22):2943-2944.
[81]Osius N,Karmaus W,Kruse H,Witten J.Exposure to polychlorinated biphenyls and levels of thyroid hormones in children.Environ Health Perspect,1999,107(10):843-849.
[82]Gupta C.Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals.Proc Soc Exp Biol Med,2000,224(2):61-68.
[83]Zhang C,Fang C,Liu L,Xia G,Qiao H.Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens.J Environ Sci Health A Tox Hazard Subst Environ Eng,2002,37(4):509-519.
[84]Hsu PC,Li MH,Guo YL.Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats.Toxicology,2003 b,187(2-3):117-126.
[85]Andric SA,Kostic TS,StojilkoVic SS,Kovacevic RZ.Inhibition of rat testicular androgenesis by a polychlorinated biphenyl mixture Aroclorl248.Biol Reprod,2000,62(6):1882-1888.
[86]Nixon A,Benghuzzi H,Cason Z.Morphometric evaluation of ovarian tissue exposed to PCB conventionally and in a sustained manner.Biomed Sci Instrum,2003,39:434-439.
[87]Ruby S,Mendoza LT,Fournier M,Brousseau P,Degas V.Reproductive system impairment of mice fed diets containing beluga whale blubber from the St Lawrence estuary and arctic populations.J Toxicol Environ HealthA,2003,66(11):1073-1085.
[88]Kholkute SD,Rodriguez J,Dukelow WR.Effects of polychlorinated biphenyls(PCBs) on in vitro fertilization in the mouse.Reprod Toxicol,1994,8(1):69-73.
[89]Wojtowicz A,Ropstad E,Gregoraszczuk E.Estrous cycle dependent changes in steroid secretion by pig ovarian cells in vitro to polychlorinated biphenyl(PCB 153).Endocr Regul,2001,35(4):223-228.
[90]Mol NM,Sorensen N,Weihe P,Andersson AM,Jorgensen N,Skakkebaek NE,Keiding N,Grandjean P.Spermaturia and serum hormone concentrations at the age of puberty in boys prenatally exposed to polychlorinated biphenyls.Eur J Endocrinol,2002,146(3):357-363.
[91]Guo YL,Hsu PC,Hsu CC,Lambert GH.Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans.Lancet,2000,356(9237):1240-1241.
[92]Harper N,Howie L,Connor K,Dickerson R,Safe S.Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice.Toxicology,1993,85(2-3):123-135.
[93]Dewailly E,Ayotte P,Bruneau S,Gingras S,Belles-Isles M,Roy R.Susceptibility to infections and immune status in Inuit infants exposed to organochlorines.Environ Health Perspect,2000,108(3):205-211.
[94]Gustavsson P,Hogstedt C.A cohort study of Swedish capacitor manufacturing workers exposed to polychlorinated biphenyls(PCBs).Am J Ind Med,1997,32(3):234-239.
[95]Sheikh MS,Ramirez A,Emmett M,Santa Ana C,Schiller LR,Fordtran JS.Role of vitamin D-dependent and vitamin D-independent mechanisms in absorption of food calcium.J Clin Invest,1988,81(1):126-132.
[96]Fischbein A,Wolff MS,Lilis R,Thornton J,Selikoff IJ.Clinical findings among PCB-exposed capacitor manufacturing workers.Ann N Y Acad Sci,1979,320:703-715.
[97]Patandin S,Lanting CI,Mulder PG,Boersma ER,Sauer PJ,Weisglas-Kuperus N.Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age.J Pediatr,1999,134(1):33-41.
[98]Van Birgelen AP,Smit EA,Kampen IM,Groeneveld CN,Fase KM,Van der Kolk J,Poiger H,Van den Berg M,Koeman JH,Brouwer A.Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism:use in risk assessment.Eur J Pharmacol,1995,293(1):77-85.
[99]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[100]Garner CE,Jefferson WN,Burka LT,Matthews HB,Newbold RR.In vitro estrogenicity of the catechol metabolites of selected polychlorinated biphenyls.Toxicol Appl Pharmacol,1999,154(2):188-197.
[101]Portigal CL,Cowell SP,Fedoruk MN,Butler CM,Rennie PS,Nelson CC.Polychlorinated biphenyls interfere with androgen-induced transcriptional activation and hormone binding.Toxicol Appl Pharmacol,2002,179(3):185-194.
[102]Kodavanti PR,Tilson HA.Neurochemical effects of environmental chemicals:in vitro and in vivo correlations on second messenger pathways.Ann N Y Acad Sci,2000,919:97-105.
[103]Bae J,Stuenkel EL,Loch-Caruso R.Stimulation of oscillatory uterine contraction by the PCB mixture Aroclor 1242 may involve increased[Ca~(2+)]i through voltage-operated calcium channels.Toxicol Appl Pharmacol,1999,155(3):261-272.
[104]Thompson CJ,Ross SM,Gaido KW.Di(w-Butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism.Endocrinology,2004,145(3):1227-1237.
[105]Song WC.Biochemistry and reproductive endocrinology of estrogen sulfotransferase.Ann N Y Acad Sci,2001,948:43-50.
[106]WHO.Combination Effects in Chemical Carcinogesis.VCH Publishern,New york,1988,5-20
[107]Broderius SJ,kahi MD,Hoglund MD.Use of joint toxic response to define the primary mode of toxic action for diverse industrial organic chemicals.Environmental Toxicology and Chemistry,1995,14(9):1591-1605.
[108]Groten JP.Mixtures and interactions.Food Chem Toxicol,2000,38(1 Suppl):S65-71.
[109]Chu I,Lecavalier P,Hakansson H,Yagminas A,Valli VE,Poon R,Feeley M.Mixture effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls congeners in rats.Chemosphere,2001,43(4-7):807-814.
[110]Wade MG,Foster WG,Younglai EV,McMahon A,Leingartner K,Yagminas A,Blakey D,Fournier M,Desaulniers D,Hughes CL.Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats:systemic,immune,and reproductive effects.Toxicol Sci,2002,67(1):131-143.
[111]Desaulniers D,Leingartner K,Musicki B,Yagminas A,Xiao GH,Cole J,Marro L,Charbonneau M,Tsang BK.Effects of postnatal exposure to mixtures of non-ortho-PCBs,PCDDs,and PCDFs in prepubertal female rats.Toxicol Sci,2003,75(2):468-480.
[112]彭双清,郝卫东,伍一军.毒理学替代法[M].第一版,北京:军事医学科学院出版社,2009,519-528.
[113]Devaux PG,Horning MG,Hill RM,Horning EC.O-benzyloximes:derivatives for the study of ketosteroids by gas chromatography.Application to urinary steroids of the newborn human.Anal Biochem,1971,41(1):70-82.
[114]Fiehn O.Metabolic networks of Cucurbita maxima phloem.Phytochemistry,2003,62(6):875-886.
[115]Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[116]Nicholson JK,Connelly J,Lindon JC,Holmes E.Metabonomics:a platform,for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[117]German JB,Bauman DE,Burrin DG,Failla ML,Freake HC,King JC,Klein S,Milner JA,Pelto GH,Rasmussen KM,Zeisel SH.Metabolomics in the opening decade of the 21st century:building the roads to individualized health.J Nutr,2004,134(10):2729-2732.
[118]Jonsson P,Bruce SJ,Moritz T,Trygg J,Sjostrom M,Plumb R,Granger J,Maibaum E,Nicholson JK,Holmes E,Antti H.Extraction,interpretation and validation of information for comparing samples in metabolic LC/MS data sets.Analyst,2005,130(5):701-707.
[119]Sandusky P,Raftery D.Use of semiselective TOCSY and the pearson correlation for the metabonomic analysis of biofluid mixtures:application to urine.Anal Chem,2005,77(23):7717-7723.
[120]Wagner S,Scholz K,Sieber M,Kellert M,Voelkel W.Tools in metabonomics:an integrated validation approach for LC-MS metabolic profiling of mercapturic acids in human urine.Anal Chem,2007,79(7):2918-2926.
[121]Sitter B,Lundgren S,Bathen TF,Halgunset J,Fjosne HE,Gribbestad IS.Comparison of HR MAS MR spectroscopic profiles of breast cancer tissue with clinical parameters.NMR Biomed,2006,19(1):30-40.
[122]Yang J,Xu G,Zheng Y,Kong H,Pang T,Lv S,Yang Q.Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases.J Chromatogr B Analyt Technol Biomed Life Sci,2004,813(1-2):59-65.
[123]Bollard ME,Stanley EG,Lindon JC,Nicholson JK,Holmes E.NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition.NMR Biomed,2005,18(3):143-162.
[124]Dettmer K,Aronov PA,Hammock BD.Mass spectrometry-based metabolomics.Mass Spectrom Rev,2007,26(1):51-78.
[125]Beckwith-Hall BM,Thompson NA,Nicholson JK,Lindon JC,Holmes E.A metabonomic investigation of hepatotoxicity using diffusion-edited 1H NMR spectroscopy of blood serum.Analyst,2003,128(7):814-818.
[126]Tang H,Wang Y,Nicholson JK,Lindon JC.Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma.Anal Biochem,2004,325(2):260-272.
[127]Webb-Robertson,BJ Lowry DF,Jarman KH,Harbo SJ,Meng QR,Fuciarelli AF,Pounds JG,Lee KM.A study of spectral integration and normalization in NMR-based metabonomic analyses.J Pharm Biomed Anal,2005,39(3-4):830-836.
[128]Aranibar N,Ott KH,Roongta V,Mueller L.Metabolomic analysis using optimized NMR and statistical methods.Anal Biochem,2006,355(1):62-70.
[129]Craig A,Cloarec O,Holmes E,Nicholson JK,Lindon JC.Scaling and normalization effects in NMR spectroscopic metabonomic data sets.Anal Chem,2006,78(7):2262-2267.
[130]Halouska S,Powers R.Negative impact of noise on the principal component analysis of NMR data.J Magn Reson,2006,178(1):88-95.
[131]van den Berg RA,Hoefsloot HC,Westerhuis JA,Smilde AK,van der Werf MJ.Centering,scaling,and transformations:improving the biological information content of metabolomics data.BMC Genomics,2006,7:142-156.
[132]Weckwerth W,Morgenthal K.Metabolomics:from pattern recognition to biological interpretation.Drug Discov Today,2005,10(22):1551-1558.
[133]Brauer DJ.A method for pattern recognition.Res Theory Nurs Pract,2006,20(4):277-289.
[134]Stoyanova R,Brown TR.NMR spectral quantitation by principal component analysis.NMR Biomed,2001,14(4):271-277.
[135]Wang Y,Bollard ME,Keun H,Antti H,Beckonert O,Ebbels TM,Lindon JC,Holmes E,Tang H,Nicholson JK.Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning 1H nuclear magnetic resonance spectroscopy of liver tissues.Anal Biochem,2003,323(1):26-32.
[136]Gavaghan CL,Wilson ID,Nicholson JK.Physiological variation in metabolic phenotyping and functional genomic studies:use of orthogonal signal correction and PLS-DA.FEBS Lett,2002,530(1-3):191-196.
[137]Eriksson L,Antti H,Gottfries J,Holmes E,Johansson E,Lindgren F,Long I,Lundstedt T,Trygg J,Wold S.Using chemometrics for navigating in the large data sets of genomics,proteomics,and metabonomics(gpm).Anal Bioanal Chem,2004,380(3):419-429.
[138]Holmes E,Nicholson JK,Tranter G.Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks.Chem Res Toxicol,2001,14(2):182-191.
[139]Lindon JC,Nicholson JK,Holmes E,Antti H,Bollard ME,Keun H,Beckonert O,Ebbels TM,Reily MD,Robertson D,Stevens GJ,Luke P,Breau AP,Cantor GH,Bible RH,Niederhauser U,Senn,H Sehlotterbeck G,Sidelmann UG,Laursen SM,Tymiak A,Car BD,Lehman-McKeeman L,Colet JM,Loukaci A,Thomas C.Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.Toxicol Appl Pharmacol,2003,187(3):137-146.
[140]Williams RE,Lock EA.Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat.Toxicology,2005,207(1):35-48.
[141]廖艳,彭双清,颜贤忠.异烟肼肝毒性的代谢组学特征研究.中国新药杂志,2007;16(4):288-292.
[142]Idborg-Bjorkman H,Edlund PO,Kvalheim OM,Schuppe-Koistinen I,Jacobsson SP.Screening of biomarkers in rat urine using LC/electrospray ionization-MS and two-way data analysis.Anal Chem,2003,75(18):4784-4792.
[143]Soga T,Baran R,Suematsu M,Ueno Y,Ikeda S,Sakurakawa T,Kakazu Y,Ishikawa T,Robert M,Nishioka T,Tomita M.Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.J Biol Chem,2006,281(24):16768-16776.
[144]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[145]Yang J,Zhao X,Liu X,Wang C,Gao P,Wang J,Li L,Gu J,Yang S,Xu G.High performance liquid chromatography-mass spectrometry for metabonomics:potential biomarkers for acute deterioration of liver function in chronic hepatitis B.J Proteome Res,2006,5(3):554-561.
[146]Lindon JC,Holmes E,Nicholson JK.Metabonomics:systems biology in pharmaceutical research and development.Curr Opin Mol Ther,2004,6(3):265-272.
[147]Lindon JC,Keun HC,Ebbels TM,Pearce JM,Holmes E,Nicholson JK.The Consortium for Metabonomic Toxicology(COMET):aims,activities and achievements.Pharmacogenomics,2005,6(7):691-699.
[148]Plumb RS,Stumpf CL,Granger JH,Castro-Perez J,Haselden JN,Dear GJ.Use of liquid chromatography/time-of-flight mass spectrometry and multivariate statistical analysis shows promise for the detection of drug metabolites in biological fluids.Rapid Commun Mass Spectrom,2003,17(23):2632-2638.
[149]Robertson DG,Reily MD,Sigler RE,Wells DF,Paterson DA,Braden TK.Metabonomics:evaluation of nuclear magnetic resonance(NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants.Toxicol Sci,2000,57(2):326-337.
[150]Shockcor JP,Holmes E.Metabonomic applications in toxicity screening and disease diagnosis.Curr Top Med Chem,2002,2(1):35-51.
[151]Gartland KP,Bonner FW,Nicholson JK.Investigations into the biochemical effects of region-specific nephrotoxins.Mol Pharmacol,1989,35(2):242-250.
[1]Poland A,Knutson JC.2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons:examination of the mechanism of toxicity.Annu Rev Pharmacol Toxicol,1982,22:517-554.
[2]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini DN,Kanagaraj P,Stanley AJ,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclor1254)induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[3]Ohbayashi H,Sasaki T,Matsumoto M,Noguchi T,Yamazaki K,Aiso S,Nagano K,Arito H,Yamamoto S.Dose- and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin on rat liver.J Toxicol Sci,2007,32(1):47-56.
[4]Jin MH,Ko HK,Hong CH,Han SW.In utero exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin affects the development of reproductive system in mouse.Yonsei Med J,2008,49(5):843-850.
[5]Ivosev G,Burton L,Bonner R.Dimensionality reduction and visualization in principal component analysis.Anal Chem,2008,80(13):4933-4944.
[6]Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica,1999,29(11):1181-1189.
[7]Raamsdonk LM,Teusink B,Broadhurst D,Zhang N,Hayes A,Walsh MC,Berden JA,Brindle KM,Kell DB,Rowland JJ,Westerhoff HV,van Dam K,Oliver SG.A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations.Nat Biotechnol,2001,19(1):45-50.
[8]Nicholson JK,Connelly J,Lindon.JC,Holmes Holmes E.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[9]倪宗瓒.医学统计学[M].第一版,北京:高等教育出版社,2004,127-129.
[10]胡良平.口腔医学科研设计与统计分析[M].第一版,北京:人民军医出版社,2007,227-231.
[11]Ramadan Z,Jacobs D,Grigorov M,Kochhar S.Metabolic profiling using principal component analysis,discriminant partial least squares,and genetic algorithms.Talanta,2006,68(5):1683-1691.
[12]Holmes E,Nicholls AW,Lindon JC,Connor SC,Connelly JC,Haselden JN,Damment SJ,Spraul M,Neidig P,Nicholson JK.Chemometric models for toxicity classification based on NMR spectra of biofluids.Chem Res Toxicol,2000,13(6):471-478.
[13]Griffin JL,Williams HJ,Sang E,Clarke K,Rae C,Nicholson JK.Metabolic profiling of genetic disorders:a multitissue(1)H nuclear magnetic resonance spectroscopic and pattern recognition study into dystrophic tissue.Anal Biochem,2001,293(1):16-21.
[14]Brindle JT,Antti H,Holmes E,Tranter G,Nicholson JK,Bethell HW,Clarke S,Schofield PM,McKilligin E,Mosedale DE,Grainger DJ.Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.Nat Med,2002,8(12):1439-1444.
[15]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[16]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[17]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[18]Gavaghan CL,Holmes E,Lenz E,Wilson ID,Nicholson JK.An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences:application to the C57BL10J and Alpk:ApfCD mouse.FEBS Lett,2000,484(3):169-174.
[19]Waterfield CJ,Turton JA,Scales MD,Timbrell JA.Investigations into the effects of various hepatotoxic compounds on urinary and liver taurine levels in rats.Arch Toxicol,1993,67(4):244-254.
[20]Griffin JL,Troke J,Walker LA,Shore RF,Lindon JC,Nicholson JK.The biochemical profile of rat testicular tissue as measured by magic angle spinning 1H NMR spectroscopy.FEBS Lett,2000,486(3):225-229.
[21]Diehl KH,Hull R,Morton D,Pfister R,Rabemampianina Y,Smith D,Vidal JM,van de Vorstenbosch C.A good practice guide to the administration of substances and removal of blood,including routes and volumes.J Appl Toxicol,2001,21(1):15-23.
[22]Nicholls AW,Holmes E,Lindon JC,Shockcor JP,Farrant RD,Haselden JN,Damment SJ,Waterfield CJ,Nicholson JK.Metabonomic investigations into hydrazine toxicity in the rat.Chem Res Toxicol,2001,14(8):975-987.
[23]Robosky LC,Robertson DG,Baker JD,Rane S,Reily MD.In vivo toxicity screening programs using metabonomics.Comb Chem High Throughput Screen,2002,5(8):651-662.
[24]Wang Y,Bollard ME,Keun H,Antti H,Beckonert O,Ebbels TM,Lindon JC,Holmes E,Tang H,Nicholson JK.Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning 1H nuclear magnetic resonance spectroscopy of liver tissues.Anal Biochem,2003,323(1):26-32.
[25]Rantalainen M,Cloarec O,Beckonert O,Wilson ID,Jackson D,Tonge R,Rowlinson R,Rayner S,Nickson J,Wilkinson RW,Mills JD,Trygg J,Nicholson JK,Holmes E.Statistically integrated metabonomic-proteomic studies on a human prostate cancer xenograft model in mice.J Proteome Res,2006,5(10):2642-2655.
[26]Robertson DG;Reily MD,Sigler RE,Wells DF,Paterson DA,Braden TK.Metabonomics:evaluation of nuclear magnetic resonance(NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants.Toxicol Sci,2000,57(2):326-337.
[27]Waters NJ,Waterfield CJ,Farrant RD,Holmes E,Nicholson JK.Integrated metabonomic analysis of bromobenzene-induced hepatotoxicity:novel induction of 5-oxoprolinosis.J Proteome Res,2006,5(6):1448-1459.
[28]Beckonert O,Keun HC,Ebbels TM,Bundy J,Holmes E,Lindon JC,Nicholson JK.Metabolic profiling,metabolomic and metabonomic procedures for NMR spectroscopy of urine,plasma,serum and tissue extracts.Nat Protoc,2007,2(11):2692-2703.
[29]Coen M,Hong YS,Clayton TA,Rohde CM,Pearce JT,Reily MD,Robertson DG,Holmes E,Lindon JC,Nicholson JK.The mechanism of galactosamine toxicity revisited;a metabonomic study.J Proteome Res,2007,6(7):2711-2719.
[30]Lindon JC,Holmes E,Nicholson JK.Metabonomics in pharmaceutical R&D.FEBS J,2007,274(5):1140-1151.
[31]Teague CR,Dhabhar FS,Barton RH,Beckwith-Hall B,Powell J,Cobain M,Singer B,McEwen BS,Lindon JC,Nicholson JK,Holmes E.Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats.J Proteome Res,2007,6(6):2080-2093.
[1]Coen M,Holmes E,Lindon JC,Nicholson JK.NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology.Chem Res Toxicol,2008,21(1):9-27.
[2]Crockford DJ,Maher AD,Ahmadi KR,Barrett A,Plumb RS,Wilson ID,Nicholson JK.1H NMR and UPLC-MS(E) statistical heterospectroscopy:characterization of drug metabolites(xenometabolome) in epidemiological studies.Anal Chem,2008,80(18):6835-6844.
[3]Lowry OH,Rosebrough NJ,Farr AL,Randall RJ.Protein measurement with the folin phenol reagent.J Biol Chem 1951;193(1):265-275.
[4]Ohkawa H,Ohishi N,Yagi K.Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.Anal Biochem 1979;95(2):351-358.
[5]Moron MS,Depierre JW,Mannervik B.Levels of glutathione,glutathione reductase and glutathione S-transferase activities in rat lung and liver.Biochim Biophys Acta,1979,582(1):67-78.
[6]Gartland KP,Beddell CR,Lindon JC,Nicholson JK.Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine.Mol Pharmacol,1991,39(5):629-642.
[7]Holmes E,Nicholls AW,Lindon JC,Ramos S,Spraul M,Neidig P,Connor SC,Connelly J,Damment SJ,Haselden J,Nicholson JK.Development of a model for classification of toxin-induced lesions using 1H NMR spectroscopy of urine combined with pattern recognition.NMR Biomed,1998,11(4-5):235-244.
[8]Nicholls AW,Holmes E,Lindon JC,Shockcor JP,Farrant RD,Haselden JN,Damment SJ,Waterfield CJ,Nicholson JK.Metabonomic investigations into hydrazine toxicity in the rat.Chem Res Toxicol,2001,14(8):975-987.
[9]Azmi J,Griffin JL,Antti H,Shore RF,Johansson E,Nicholson JK,Holmes E.Metabolic trajectory characterisation of xenobiotic-induced hepatotoxic lesions using statistical batch processing of NMR data.Analyst,2002,127(2):271-276.
[10]Keun HC,Ebbels TM,Bollard ME,Beckonert O,Antti H,Holmes E,Lindon JC,Nicholson JK.Geometric trajectory analysis of metabolic responses to toxicity can define treatment specific profiles.Chem Res Toxicol,2004,17(5):579-587.
[11]Siculella L,Sabetta S,di Summa R,Leo M,Giudetti AM,Palmieri F,Gnoni GV.Starvation-induced posttranscriptional control of rat liver mitochondrial citrate carrier expression.Biochem Biophys Res Commun,2002,299(3):418-423.
[12]Connor SC,Wu W,Sweatman BC,Manini J,Haselden JN,Crowther DJ,Waterfield CJ.Effects of feeding and body weight loss on the 1H-NMR-based urine metabolic profiles of male Wistar Han rats:implications for biomarker discovery.Biomarkers,2004,9(2):156-179.
[13]Foxall PJ,Bending MR,Gartland KP,Nicholson JK.Acute renal failure following accidental cutaneous absorption of phenol:application of NMR urinalysis to monitor the disease process.Hum Toxicol,1989,8(6):491-496.
[14]Buckalew Jr VM.Nephrolithiasis in renal tubular acidosis.J Urol,1989,141(3 Pt 2):731-737.
[15]Holmes E,Nicholson JK,Nicholls AW,Lindon JC.The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine.Chemometr Intell Lab Syst,1998,44(1-2):245-255.
[16]Galvani M,Ferrini D,Puggioni R,Ruggeri S,Ottani F.New markers for early diagnosis of acute myocardial infarction.Int J Cardiol,1998,65(Suppl 1):S17-22.
[17]Griffin JL,Troke J,Walker LA,Shore RF,Lindon JC,Nicholson JK.The biochemical profile of rat testicular tissue as measured by magic angle spinning 1H NMR spectroscopy.FEBS Lett,2000,486(3):225-229.
[18]Sharp RR,Barrett JC.The environmental genome project:ethical,legal,and social implications.Environ Health Perspect,2000,108(4):279-281.
[19]Gatley SJ,Sherratt HS.The synthesis of hippurate from benzoate and glycine by rat liver mitochondria.Submitochondrial localization and kinetics.Biochem J,1977,166(1):39-47.
[20]Enan E,Lasley B,Stewart D,Overstreet J,Vandevoort CA.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity.Reprod Toxicol,1996,10(3):191-198.
[21]Williams RE,Jacobsen M,Lock EA.1H NMR pattern recognition and 31P NMR studies with d-Serine in rat urine and kidney,time-and dose-related metabolic effects.Chem Res Toxicol,2003,16(10):1207-1216.
[22]Lenz EM,Bright J,Knight R,Wilson ID,Major H.A metabonomic investigation of the biochemical effects of mercuric chloride in the rat using 1H NMR and HPLC-TOF/MS:time dependent changes in the urinary profile of endogenous metabolites as a result of nephrotoxicity.Analyst,2004,129(6):535-541.
[23]Lenz EM,Bright J,Knight R,Westwood FR,Davies D,Major H,Wilson ID.Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat.Biomarkers,2005,10(2-3): 173-187.
[24]Holmes E,Bonner FW,Nicholson JK.Comparative studies on the nephrotoxicity of 2-bromoethanamine hydrobromide in the Fischer 344 rat and the multimammate desert mouse(Mastomys natalensis).Arch Toxicol,1995,70(2):89-95.
[25]Williams RE,Cottrell L,Jacobsen M,Bandara LR,Kelly MD,Kennedy S,Lock EA.1H-Nuclear magnetic resonance pattern recognition studies with N-phenylanthranilic acid in the rat:time- and dose-related metabolic effects.Biomarkers,2003,8(6):472-490.
[26]Li XJ,Feng JH,Zhang SR,Pei FK,Chen X,Nie YX.Effect of rare earth element on the metabolism in rats by high resolution proton nuclear magnetic resonance spectroscopy.Chinese J Anal Chem,2000,28(12):1472-1475.
[27]Sanins SM,Nicholson JK,Elcombe C,Timbrell JA.Hepatotoxin-induced hypertaurinuria:a proton NMR study.Arch Toxicol,1990,64(5):407-411.
[28]Waterfield CJ,Turton JA,Scales MD,Timbrell JA.Investigations into the effects of various hepatotoxic compounds on urinary and liver taurine levels in rats.Arch Toxicol,1993,67(4):244-254.
[29]Nicholson JK,Connelly J,Lindon JC,Holmes Holmes E.Metabonomics:a platform for studying drug toxicity and gene function.Nat Rev Drug Discov,2002,1(2):153-161.
[1]Moennikes O,Loeppen S,Buchmann A,Andersson P,Ittrich C,Poellinger L,Schwarz MA.Constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice.Cancer Res,2004,64(14):4707-4710.
[2]Baba T,Mimura J,Nakamura N,Harada N,Yamamoto M,Morohashi K,Fujii-Kuriyama Y.Intrinsic function of the aryl hydrocarbon(dioxin) receptor as a key factor in female reproduction.Mol Cell Biol,2005,25(22):10040-10051.
[3]Pollenz RS.The mechanism of AH receptor protein down-regulation(degradation) and its impact on AH receptor-mediated gene regulation.Chem Biol Interact,2002,141(1-2):41-61.
[4]Andersson P,Ridderstad A,McGuire J,Pettersson S,Poellinger L,Hanberg A.A constitutively active aryl hydrocarbon receptor causes loss of peritoneal B1 cells.Biochem Biophys Res Commun,2003,302(2):336-341.
[5]Boutros PC,Moffat ID,Franc MA,Tijet N,Tuomisto J,Pohjanvirta R,Okey AB.Dioxin-responsive AHRE-Ⅱ gene battery:identification by phylogenetic footprinting.Biochem Biophys Res Commun,2004,321(3):707-715.
[6]Nebert DW,Dalton TP,Okey AB,Gonzalez FJ.Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.J Biol Chem,2004,279(23):23847-23850.
[7]Nebert DW,Roe AL,Dieter MZ,Solis WA,Yang Y,Dalton TP.Role of the aromatic hydrocarbon receptor and[Ah]gene battery in the oxidative stress response,cell cycle control,and apoptosis.Biochem Pharmacol,2000,59(1):65-85.
[8]Mimura J,Fujii-Kuriyama Y.Functional role of AhR in the expression of toxic effects by TCDD.Biochim Biophys Acta,2003,1619(3):263-268.
[9]Fujii-Kuriyama Y,Mimura J.Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes.Biochem Biophys Res Commun,2005,338(1):311-317.
[10]Knerr S,Schaefer J,Both S,Mally A,Dekant W,Schrenk D.2,3,7,8-tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells.Mol Nutr Food Res,2006,50(4-5):378-384.
[11]Hu W,Sorrentino C,Denison MS,Kolaja K,Fielden MR.Induction of cypl al is a nonspecific biomarker of aryl hydrocarbon receptor activation:results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro.Mol Pharmacol,2007,71(6):1475-1486.
[12]Chubb LS,Andersen ME,Broccardo CJ,Legare ME,Billings RE,Dean CE,Hanneman WH.Regional induction of CYP 1A1 in rat liver following treatment with mixtures of PCB 126 and PCB 153.Toxicol Pathol,2004,32(4):467-473.
[13]Leung YK,Lau KM,Mobley J,Jiang Z,Ho SM.Overexpression of cytochrome P450 1A1 and its novel spliced variant in ovarian cancer cells:alternative subcellular enzyme compartmentation may contribute to carcinogenesis.Cancer Res,2005,65:3726-3734.
[14]Gauger KJ,Giera S,Sharlin DS,Bansal R,Iannacone E,Zoeller RT.Polychlorinated biphenyls 105 and 118 form thyroid hormone receptor agonists after cytochrome P4501A1 activation in rat pituitary GH3 cells.Environ Health Perspect,2007,115(11):1623-1630.
[15]Lin PH,Lin CH,Huang CC,Chuang MC,Lin P.2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) induces oxidative stress,DNA strand breaks,and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines.Toxicol Lett,2007,172(3):146-158.
[16]Sridevi N,Venkataraman P,Senthilkumar K,Krishnamoorthy G,Arunakaran J.Oxidative stress modulates membrane bound ATPases in brain regions of PCB(Aroclor1254) exposed rats:Protective role of alpha-tocopherol.Biomed Pharmacother,2007,61(7):435-440.
[17]Chen ZH,Hurh YJ,Na HK,Kim JH,Chun YJ,Kim DH,Kang KS,Cho MH,Surh YJ.Resveratrol inhibits TCDD-induced expression of CYP 1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells.Carcinogenesis,2004,25(10):2005-2013.
[18]Marlowe JL,Puga A.Aryl hydrocarbon receptor,cell cycle regulation,toxicity,and tumorigenesis.J Cell Biochem,2005,96(6):1174-1184.
[19]Tijet N,Boutros PC,Moffat ID,Okey AB,Tuomisto J,Pohjanvirta R.Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries.Mol Pharmacol,2006,69(1):140-153.
[20]Xu L,Li AP,Kaminski DL,Ruh MF.2,3,7,8 Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes.Chem Biol Interact,2000,124(3):173-189.
[21]Henry TR,Nesbit DJ,Heideman W,Peterson RE.Relative potencies of polychlorinated dibenzo-p-dioxin,dibenzofuran,and biphenyl congeners to induce cytochrorne P4501A mRNA in a zebrafish liver cell line.Environ Toxicol Chem,2001,20(5):1053-1058.
[22]Kono Y,Okada S,Tazawa Y,Kanzaki S,Mura T;Ueta E,Nanba E,Otsuka Y.Effect of lactational exposure to 1,2,3,4-tetrachlorodibenzo-p-dioxin on cytochrome P-450 1A1 mRNA in the neonatal rat liver: quantitative analysis by the competitive RT-PCR method.Pediatr Int,2001,43(5):458-464.
[23]Twaroski TP,O'Brien ML,Larmonier N,Glauert HP,Robertson LW.Polychlorinated biphenyl-induced effects on metabolic enzymes,AP-1 binding,vitamin E,and oxidative stress in the rat liver.Toxicol Appl Pharmacol,2001,171(2):85-93.
[24]Hassoun EA,Wang H,Abushaban A,Stohs SJ.Induction of oxidative stress in the tissues of rats after chronic exposure to TCDD,2,3,4,7,8-pentachlorodibenzofuran,and 3,3',4,4',5-pentachlorobiphenyl.J Toxicol Environ Health A,2002,65(12):825-842.
[25]Kern PA,Fishman RB,Song W,Brown AD,Fonseca V.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on oxidative enzymes in adipocytes and liver.Toxicology,2002,171(2-3):117-125.
[26]Latchoumycandane C,Chitra KC,Mathur PP.The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antioxidant system in mitochondrial and microsomal fractions of rat testis.Toxicology,2002,171(2-3):127-135.
[27]Murugesan P,Senthilkumar J,Balasubramanian K,Aruldhas MM,Arunakaran J.Impact of polychlorinated biphenyl Aroclor1254 on testicular antioxidant system in adult rats.Hum Exp Toxicol,2005,24(2):61-66.
[28]Muthuvel R,Venkataraman P,Krishnamoorthy G,Gunadharini DN,Kanagaraj P,Stanley AJ,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.Antioxidant effect of ascorbic acid on PCB(Aroclorl254) induced oxidative stress in hypothalamus of albino rats.Clin Chim Acta,2006,365(1-2):297-303.
[29]Venkataraman P,Muthuvel R,Krishnamoorthy G,Arunkumar A,Sridhar M,Srinivasan N,Balasubramanian K,Aruldhas MM,Arunakaran J.PCB(Aroclor1254) enhances oxidative damage in rat brain regions:Protective role of ascorbic acid.Neurotoxicology,2007,28(3):490-498.
[30]Aas E,Baussant T,Balk L,Liewenborg B,Andersen OK.PAH metabolites in bile,cytochrome P4501A and DNA adducts as environmental risk parameters for chronic oil exposure:a laboratory experiment with Atlantic cod.Aquat Toxicol,2000,51(2):241-258.
[31]Kostka G.The use of biomarkers in the assessment of health risk from environmental exposure to chemical carcinogens.Rocz Panstw Zakl Hig,2003,54(S1):30-31.
[32]Borras M,Nadal J.Biomarkers of genotoxicity and other end-points in an integrated approach to environmental risk assessment.Mutagenesis,2004,19:165-168.
[33]Cossu C,Doyotte A,Babut M,Exinger A,Vasseur P.Antioxidant biomarkers in freshwater bivalves,Unio tumidus,in response to different contamination profiles of aquatic sediments.Ecotoxicol Environ Saf,2000, 45(2):106-121.
[34]den Besten PJ,Valk S,van Weerlee E,Nolting RF,Postma JF,Everaarts JM.Bioaccumulation and biomarkers in the sea star Asterias rubens(Echinodermata:Asteroidea):a North Sea field study.Mar Environ Res,2001,51(4):365-387.
[35]Pascual P,Pedrajas JR,Toribio F,Lopez-Barea J,Peinado J.Effect of food deprivation on oxidative stress biomarkers in fish(Spams aurata).Chem Biol Interact,2003,145(2):191-199.
[36]Cheung CC,Siu WH,Richardson BJ,De Luca-Abbott SB,Lam PK.Antioxidant responses to benzo[a]pyrene and Aroclor 1254 exposure in the green-lipped mussel,Perna viridis.Environ Pollut,2004,128(3):393-403.
[37]Cheung CC,Zheng GJ,Lam PK,Richardson BJ.Relationships between tissue concentrations of chlorinated hydrocarbons(polychlorinated biphenyls and chlorinated pesticides) and antioxidative responses of marine mussels,Perna viridis.Mar Pollut Bull,2002,45(1-12):181-191.
[38]Oruc EO,Sevgiler Y,Uner N.Tissue-specific oxidative stress responses in fish exposed to 2,4-D and azinphosmethyl.Comp Biochem Physiol C Toxicol Pharmacol,2004,137(1):43-51.
[39]Verweij F,Booij K,Satumalay K,van der Molen N,van der Oost R.Assessment of bioavailable PAH,PCB and OCP concentrations in water,using semipermeable membrane devices(SPMDs),sediments and caged carp.Chemosphere,2004,54(11):1675-1689.
[40]Kammenga JE,Arts MSJ,Oude-Breuil WJM.HSP60 as a potential biomarker of toxic stress in the nematode plectus acuminatus.Arch Environ Contam Toxicol,1998,34(3):253-258.
[41]Pirillo A,Norata GD,Zanelli T,Catapano AL.Overexpression of Inducible Heat Shock Protein 70 in COS-1 Cells Fails to Protect From Cytotoxicity of Oxidized LDLs.Arterioscler Thromb Vasc Biol,2001,21(3):348-354.
[42]Miyabara EH,Martin JL,Griffin TM,Moriscot AS,Mestril R.Overexpression of inducible 70-kDa heat shock protein in mouse attenuates skeletal muscle damage induced by cryolesioning.Am J Physiol Cell Physiol,2006,290(4):C1128-C1138.
[43]Chu I,Lecavalier P,Hakansson H,Yagminas A,Valli VE,Poon P,Feeley M.Mixture effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls congeners in rats.Chemosphere,2001,43(4-7):807-814.
[44]Wade MG,Foster WG,Younglai EV,McMahon A,Leingartner K,Yagminas A,Blakey D,Fournier M,Desaulniers D,Hughes CL.Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats:systemic,immune,and reproductive effects.Toxicol Sci,2002,67(1):131-143.
[45]Desaulniers D,Leingartner K,Musicki B,Yagminas A,Xiao GH,Cole J,Marro L,Charbonneau M,Tsang BK.Effects of postnatal exposure to mixtures of non-ortho-PCBs,PCDDs,and PCDFs in prepubertal female rats.Toxicol Sci,2003,75(2):468-480.
[46]Crofton KM,Craft ES,Hedge JM,Gennings C,Simmons JE,Carchman RA,Carter Jr WH,DeVito MJ.Thyroid-hormone-disrupting chemicals:evidence for dose-dependent additivity or synergism.Environ Health Perspect,2005,113(11):1549-1554.
[47]van Birgelen AP,Fase KM,van der Kolk J,Poiger H,Brouwer A,Seinen W,van den Berg M.Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.Environ Health Perspect,1996,104(5):550-557.
[48]Sugatani J,Kojima H,Ueda A,Kakizaki S,Yoshinari K,Gong QH,Owens IS,Negishi M,Sueyoshi T.The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1gene and regulation by the nuclear receptor CAR.Hepatology,2001,33(5):1232-1238.
[49]Craft ES,DeVito MJ,Crofton KM.Comparative responsiveness of hypothyroxinemia and hepatic enzyme induction in long-evans rats versus C57BL/6J mice exposed to TCDD-like and phenobarbital-like polychlorinated biphenyl congeners.Toxicol Sci,2002,68(2):372-380.
[50]Tabb MM,Kholodovych V,Grun F,Zhou C,Welsh WJ,Blumberg B.Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor(SXR).Environ Health Perspect,2004,112(2):163-169.
[51]Bonefeld-Jorgensen EC,Andersen HR,Rasmussen TH,Vinggaard AM.Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.Toxicology,2001,158(3):141-153.
[52]Chen G,Bunce NJ.Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathway.Environ Toxicol,2004,19(5):480-489.
[53]Snh J,Kang JS,Yang KH,Kaminski NE.Antagonism of aryl hydrocarbon receptor-dependent induction of CYP1A1 and inhibition of IgM expression by di-ortbo-substituted polychlorinated biphenyls.Toxicol Appl Pharmacol,2003,187(1):11-21.
[54]Petrulis JR,Bunce NJ.Competitive behavior in the interactive toxicology of halogenated aromatic compounds.J Biochem Mol Toxicol,2000,14(2):73-81.
[55]Groten JP.Mixtures and interactions.Food Chem Toxicol,2000,38(1 Suppl):S65-71.