Interstrain Differences in the Liver Effects of Trichloroethylene in a Multistrain Panel of Inbred Mice
Interstrain Differences in the Liver Effects of Trichloroethylene in a Multistrain Panel of Inbred Mice
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DOI：
10.1093/toxsci/kfq362
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发表时间：
2011-03-01
影响因子：
3.8
通讯作者：
Rusyn, Ivan
中科院分区：
文献类型：
--
作者：
Bradford, Blair U.;Lock, Eric F.;Rusyn, Ivan
三氯乙烯（TCE）是一种广泛使用的工业化学品，也是一种常见的环境污染物。它是啮齿类动物中众所周知的致癌物，也是人类中可能的致癌物。利用小鼠近交系进行的研究为了解TCE反应差异的代谢和遗传基础提供了独特的机会。我们测试的假设，应变和肝脏特异性毒性效应的TCE的遗传控制和毒性和易感性的机制，可以通过探索响应TCE使用不同的面板近交系小鼠品系。TCE（2100 mg/kg）或玉米油溶剂通过管饲法给予15种小鼠品系的6- 8周龄雄性小鼠。在给药后2、8和24 h采集血清和肝脏，分析TCE代谢产物、肝细胞损伤和肝脏基因表达。TCE代谢，从个人的氧化和共轭代谢产物的水平明显，菌株之间的差异很大。TCE对肝脏转录组的治疗特异性作用强烈依赖于遗传背景。过氧化物酶体增殖物激活受体介导的分子网络，由已知由TCE诱导的代谢基因组成，代表了TCE治疗在小鼠肝脏中依赖于遗传背景的一些最显著的分子效应。相反，TCE治疗改变肝脏中的细胞死亡、肝坏死和免疫介导的反应途径，在很大程度上与遗传背景无关。这些研究提供了对TCE诱导的毒性机制的更好理解，这些毒性机制锚定在代谢和基因型-表型相关性上，这些相关性可能定义易感性或耐药性。
Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be uncovered by exploring responses to TCE using a diverse panel of inbred mouse strains. TCE (2100 mg/kg) or corn oil vehicle was administered by gavage to 6- to 8-week-old male mice of 15 mouse strains. Serum and liver were collected at 2, 8, and 24 h postdosing and were analyzed for TCE metabolites, hepatocellular injury, and gene expression of liver. TCE metabolism, as evident from the levels of individual oxidative and conjugative metabolites, varied considerably between strains. TCE treatment-specific effect on the liver transcriptome was strongly dependent on genetic background. Peroxisome proliferator-activated receptor-mediated molecular networks, consisting of the metabolism genes known to be induced by TCE, represent some of the most pronounced molecular effects of TCE treatment in mouse liver that are dependent on genetic background. Conversely, cell death, liver necrosis, and immune-mediated response pathways, which are altered by TCE treatment in liver, are largely genetic background independent. These studies provide better understanding of the mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that may define susceptibility or resistance.