Population-based dose-response analysis of liver transcriptional response to trichloroethylene in mouse.
Population-based dose-response analysis of liver transcriptional response to trichloroethylene in mouse.
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DOI：
10.1007/s00335-018-9734-y
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Rusyn I
中科院分区：
文献类型：
--
作者：
Venkatratnam A;House JS;Konganti K;McKenney C;Threadgill DW;Chiu WA;Aylor DL;Wright FA;Rusyn I
基因表达的研究在毒理学中很常见，并为化学品不良反应的机理理解提供了重要线索。大多数先前的研究都是在单一菌株或细胞系中进行的;然而，基因表达受到遗传背景的严重影响，这些基因型表达差异可能是响应化学毒性的个体间变异的关键驱动因素。在这项研究中，我们假设，遗传多样性的协作杂交（CC）小鼠种群可用于获得洞察力，并提出化学暴露的剂量和遗传背景依赖性效应的机制假说。使用模型肝毒物三氯乙烯（TCE）对这一假设进行了检验。在给药后24小时评价肝脏对TCE暴露的转录反应。研究了TCE及其主要氧化代谢物三氯乙酸（TCA）的转录组剂量反应。正如预期的那样，过氧化物酶体和脂肪酸代谢相关途径是所有菌株中最具剂量响应性的富集途径。然而，近一半的三氯乙烯诱导的肝脏转录干扰是应变依赖性的，有大量的证据表明应变/剂量相互作用，包括在过氧化物酶体信号相关的途径。这些效应在TCE给药剂量和TCA肝脏水平之间高度一致。在途径水平上对基因表达进行的剂量反应分析得出的出发点与传统毒理学研究得出的非癌症和癌症效应的出发点相似。表达-基因型-剂量关系的映射揭示了一些显著的关联;然而，TCE对肝脏中基因表达的影响似乎是高度多基因的性状，这对定位映射具有挑战性。这项研究强调了以小鼠群体为基础的研究在评估毒理学反应的个体间差异方面的有用性，但警告说，由于基因-暴露-剂量关系的复杂性，遗传图谱可能具有挑战性。
Studies of gene expression are common in toxicology and provide important clues to mechanistic understanding of adverse effects of chemicals. Most prior studies have been performed in a single strain or cell line; however, gene expression is heavily influenced by the genetic background, and these genotype-expression differences may be key drivers of inter-individual variation in response to chemical toxicity. In this study, we hypothesized that the genetically-diverse Collaborative Cross (CC) mouse population can be used to gain insight and suggest mechanistic hypotheses for the dose- and genetic background-dependent effects of chemical exposure. This hypothesis was tested using a model liver toxicant trichloroethylene (TCE). Liver transcriptional responses to TCE exposure were evaluated 24 hours after dosing. Transcriptomic dose-responses were examined for both TCE and its major oxidative metabolite trichloroacetic acid (TCA). As expected, peroxisome- and fatty acid metabolism-related pathways were among the most dose-responsive enriched pathways in all strains. However, nearly half of the TCE-induced liver transcriptional perturbation was strain-dependent, with abundant evidence of strain/dose interaction, including in the peroxisomal signaling-associated pathways. These effects were highly concordant between the administered TCE dose and liver levels of TCA. Dose-response analysis of gene expression at the pathway level yielded points of departure similar to those derived from the traditional toxicology studies for both non-cancer and cancer effects. Mapping of expression-genotype-dose relationships revealed some significant associations; however, the effects of TCE on gene expression in liver appear to be highly polygenic traits that are challenging to positionally map. This study highlights the usefulness of mouse population-based studies in assessing inter-individual variation in toxicological responses, but cautions that genetic mapping may be challenging because of the complexity in gene-exposure-dose relationships.
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影响因子：
10.4
作者：
Bronley-DeLancey A;McMillan DC;McMillan JM;Jollow DJ;Mohr LC;Hoel DG
通讯作者：
Hoel DG
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
2.5
作者：
Churchill, Gary A.;Gatti, Daniel M.;Munger, Steven C.;Svenson, Karen L.
通讯作者：
Svenson, Karen L.
影响因子：
3.8
作者：
Andersen, Melvin E.;Clewell, Harvey J., III;Thomas, Russell S.
通讯作者：
Thomas, Russell S.
影响因子：
3.8
作者：
Chiu, Weihsueh A.;Ginsberg, Gary L.
通讯作者：
Ginsberg, Gary L.