Venkatratnam Abhishek, House John S, Konganti Kranti, McKenney Connor, Threadgill David W, Chiu Weihsueh A, Aylor David L, Wright Fred A, Rusyn Ivan
Department of Veterinary Integrative Biosciences, Texas A&M University, 4458 TAMU, College Station, Texas, 77843, USA.
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina, 27599, USA.
Mamm Genome. 2018 Feb;29(1-2):168-181. doi: 10.1007/s00335-018-9734-y. Epub 2018 Jan 20.
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 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 h 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.
基因表达研究在毒理学中很常见，为深入理解化学物质的不良反应机制提供了重要线索。大多数先前的研究是在单一品系或细胞系中进行的；然而，基因表达受到遗传背景的严重影响，这些基因型与表达的差异可能是个体对化学毒性反应差异的关键驱动因素。在本研究中，我们假设遗传背景多样的协作杂交小鼠群体可用于深入了解化学物暴露的剂量和遗传背景依赖性效应，并提出机制假说。使用模型肝毒物三氯乙烯（TCE）对这一假说进行了验证。给药24小时后评估肝脏对TCE暴露的转录反应。研究了TCE及其主要氧化代谢产物三氯乙酸（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品系中剂量反应最明显的富集途径。然而，近一半的TCE诱导的肝脏转录扰动具有品系依赖性，有大量品系/剂量相互作用的证据，包括过氧化物酶体信号相关途径。这些效应在给药的TCE剂量和肝脏TCA水平之间高度一致。在途径水平上对基因表达进行剂量反应分析得出的起始点与传统毒理学研究中非癌症和癌症效应得出的起始点相似。表达-基因型-剂量关系图谱揭示了一些显著关联；然而，TCE对肝脏基因表达的影响似乎是高度多基因性状，难以进行定位图谱分析。这项研究强调了基于小鼠群体的研究在评估毒理学反应个体差异方面的有用性，但也提醒由于基因暴露-剂量关系的复杂性，基因定位可能具有挑战性。
