Genetic Factors that Influence Arsenic Toxicity

项目摘要/摘要 该项目是对系统毒理学原理的证明，是一种新的化学安全评价方法， 在遗传多样性动物模型的背景下集成分子、细胞和生理数据 开发关于导致化学品不良后果的关键分子事件的可测试假说 曝光。该项目旨在利用两种强大的基于种群的模式生物的潜力 资源，合作杂交(CC)和多样性杂交(DO)小鼠，以研究遗传学在 使人对化学物质暴露易感。通过一系列使用砷的综合实验 在小鼠和细胞系中暴露，将评估毒理学反应的分子遗传学基础。这 该项目将测试在定量环境扰动的背景下进行遗传分析的假设 将揭示对化学暴露做出反应的多个、新颖和多样化的生化网络。这个 拟议的一整套实验将能够发现和验证不良结果途径 通过三个具体目标。AIM 1将评估用不同基因的狗进行动物试验的研究设计 小鼠包括毒性评估所需的样本量。G×E遗传基因座将被绘制并 合并到预测计算模型中，将提出可检验的假设进行验证。 Aim 2将对体外原代细胞培养进行平行的、人群水平的砷暴露研究，以确定 利用具有生理信息的细胞表型分析易感性和抗药性的遗传因素。 在体外砷暴露研究中产生的数据将使我们能够确定 细胞毒性、遗传毒性和氧化应激在细胞检测中对 发现在整个生物体中驱动易感性和/或反应的分子途径。目标3将 确定肾砷中毒的关键机制。这项研究将为砷的影响建立一个模型 对肾脏的暴露以预测取决于遗传背景的结果。总体而言，这一新的 使用DO小鼠的毒理学方法将通过结合化学物质来解决基本的生物学问题 对遗传变异的干预。它将在多个分子和分子水平上建立因果关系 生理结果，以产生与临床翻译相关的结果。

PROJECT SUMMARY/ABSTRACT This project is a proof of principle of systems toxicology, a new approach to chemical safety evaluation that integrates molecular, cellular, and physiological data in the context of a genetically diverse animal model to develop testable hypotheses about the key molecular events leading to adverse outcomes following chemical exposure. The project aims to capitalize on the potential of two powerful population-based model organism resources, the Collaborative Cross (CC) and Diversity Outbred (DO) mice, to study the role of genetics in conferring susceptibility to chemical exposures. Through an integrated set of experiments using arsenic exposure in mice and cell lines, the molecular genetic basis of toxicological responses will be evaluated. This project will test the hypothesis that genetic analysis in the context of a quantitative environmental perturbation will reveal multiple, novel, and diverse biochemical networks that respond to chemical exposure. The proposed integrated set of experiments will enable the discovery and validation of adverse outcome pathways through three specific aims. Aim 1 will evaluate study designs for animal testing with genetically diverse DO mice including sample size requirements for toxicity evaluation. G x E genetic loci will be mapped and incorporated into predictive computational models, and testable hypotheses will be proposed for validation. Aim 2 will conduct a parallel, population-level arsenic exposure study of in vitro primary cell cultures to identify genetic factors underlying susceptibility and resistance using physiologically informative cellular phenotypes. The data generated in the in vitro arsenic exposure study will allow determination of the extent to which cytotoxicity, genotoxicity, and oxidative stress in cellular assays are physiologically informative for the discovery of molecular pathways that drive susceptibility and/or response in the whole organism. Aim 3 will identify key mechanisms in renal arsenic toxicity. This study will generate a model for the effect of arsenic exposure on the kidney to predict outcomes that are contingent on genetic background. Collectively, this new approach to toxicology using DO mice will address fundamental biological questions by combining chemical interventions with genetic variation. It will establish causal pathways across multiple levels of molecular and physiological outcomes to yield results with relevance to clinical translation.