Genetic Factors that Influence Arsenic Toxicity

项目总结/摘要 该项目是系统毒理学原理的证明，是化学品安全评价的一种新方法， 在遗传多样性动物模型的背景下整合分子、细胞和生理数据， 发展可检验的假设，关于化学治疗后导致不良后果的关键分子事件 exposure.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，协作杂交（CC）和多样性远交（DO）小鼠，研究遗传学在 使其对化学品暴露敏感。通过一系列的实验， 通过在小鼠和细胞系中暴露，将评价毒理学反应的分子遗传基础。这 该项目将测试的假设，遗传分析的背景下，一个定量的环境扰动 将揭示多种多样的，新颖的，多样的生化网络，对化学暴露作出反应。的 建议的一套综合实验将能够发现和验证不利的结果途径 通过三个具体目标。目标1将评价具有遗传多样性DO的动物试验的研究设计 小鼠，包括毒性评价的样本量要求。将绘制G x E基因座， 将被纳入预测计算模型，并提出可检验的假设进行验证。 目的2将进行一项平行的、人群水平的体外原代细胞砷暴露研究， 使用生理信息细胞表型的易感性和抗性的遗传因素。 在体外砷暴露研究中产生的数据将允许确定 细胞试验中的细胞毒性、遗传毒性和氧化应激对于 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。这项研究将产生一个模型的影响，砷 暴露在肾脏上，以预测取决于遗传背景的结果。总体而言，这一新 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。 干预遗传变异。它将在多个分子水平上建立因果通路， 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.