Genetic Factors that Influence Arsenic Toxicity

PROJECT SUMMARY/ABSTRACTThis project is a proof of principle of systems toxicology, a new approach to chemical safety evaluation thatintegrates molecular, cellular, and physiological data in the context of a genetically diverse animal model todevelop testable hypotheses about the key molecular events leading to adverse outcomes following chemicalexposure. The project aims to capitalize on the potential of two powerful population-based model organismresources, the Collaborative Cross (CC) and Diversity Outbred (DO) mice, to study the role of genetics inconferring susceptibility to chemical exposures. Through an integrated set of experiments using arsenicexposure in mice and cell lines, the molecular genetic basis of toxicological responses will be evaluated. Thisproject will test the hypothesis that genetic analysis in the context of a quantitative environmental perturbationwill reveal multiple, novel, and diverse biochemical networks that respond to chemical exposure. Theproposed integrated set of experiments will enable the discovery and validation of adverse outcome pathwaysthrough three specific aims. Aim 1 will evaluate study designs for animal testing with genetically diverse DOmice including sample size requirements for toxicity evaluation. G x E genetic loci will be mapped andincorporated 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 identifygenetic 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 whichcytotoxicity, genotoxicity, and oxidative stress in cellular assays are physiologically informative for thediscovery of molecular pathways that drive susceptibility and/or response in the whole organism. Aim 3 willidentify key mechanisms in renal arsenic toxicity. This study will generate a model for the effect of arsenicexposure on the kidney to predict outcomes that are contingent on genetic background. Collectively, this newapproach to toxicology using DO mice will address fundamental biological questions by combining chemicalinterventions with genetic variation. It will establish causal pathways across multiple levels of molecular andphysiological outcomes to yield results with relevance to clinical translation.