The mouse has become a powerful model organism for biomedical research in the post-genome era. The decades of research to uncover linkages between the genome and phenome using mouse models led to accumulation of a large body of knowledge on the genetic diversity and gene-environment interactions that is yet to be matched for any other mammal, including humans. This application is proposing a new systems biology approach for molecular dissection and discovery of biological pathways leading to trichloroethylene (TCE)-induced liver and kidney toxicity. Since the metabolism of TCE is qualitatively similar in mice and man, but the toxicity outcomes are thought to differ, mouse inbred strains afford a unique opportunity to understand both molecular and genetic basis for differences in responses to TCE. We will test the hypothesis that apparent species- and organ-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be successfully elucidated using a panel of mouse inbred strains. A set of 16 mouse inbred strains being sequenced by the NIEHS Center for Rodent Genetics will be used in an experimental design that recapitulates several acute, sub-chronic and chronic studies with TCE conducted by the National Toxicology Program. First, we will determine if TCE metabolism is dependent upon genetic differences between mouse strains. Next, we will establish if strain-specific differences in TCE metabolism affects the organ-selective dose-response toxicity outcomes following sub-chronic exposure. Finally, we will test if strain-specific differences in TCE metabolism and toxicity affect the carcinogenic potential. The molecular and biochemical changes involved in the mechanisms of toxic injury and differences in metabolism of TCE will be determined using metabolomic, genomic and classical toxicology approaches. These studies will lead to a better understanding of the dose-response and mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that define susceptibility or resistance, and will identify relevant animal models, novel biomarkers and endpoints that can be used in animal and human studies.
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