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Principal Investigator: Weinhouse, Caren
Institute Receiving Award Oregon Health & Science University
Location Portland, OR
Grant Number K01ES032044
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Aug 2020 to 31 Jul 2024
DESCRIPTION (provided by applicant): PROJECT SUMMARY Environmental toxicant exposures correlate with changes to DNA methylation, or chemical modifications to DNA that regulate gene expression, but the mechanisms underlying these correlations are unknown. DNA methylation can differ in genetically identical individuals, allowing different phenotypes to develop from identical genotypes following exposure. These results suggest specific cellular responses to chemicals that lead to environmental differences in phenotype. In addition, unexposed genetically identical individuals show variability in DNA methylation, indicating that some differences are stochastic (i.e., probabilistic). In genetically different individuals, DNA methylation patterns correlate highly with genotype, both in the absence and presence of chemical exposure, indicating that some DNA methylation is under genetic control, and that some DNA methylation responses to chemicals occur in some genotypes more than others (gene-environment interactions). Here, I will test the central hypothesis that these four sources each explain equal proportions of the total DNA methylation response in genotypically different mice with developmental exposure to a model chemical, the heavy metal methylmercury (MeHg). MeHg is an ideal model chemical because it is of strong public health concern, there are known phenotypic differences in exposed humans and rodents, and MeHg does not cause DNA damage, which independently affects DNA methylation. My career development goal is to integrate new training in statistical genetics with my background in environmental epigenetics to do research that is both mechanistic and translatable to human populations. I will leverage a classic F2 intercross design between two inbred mouse strains, one susceptible (CAST/EiJ) and one resistant (C57BL/6J) to MeHg neurotoxicity. F1 hybrid mice are generated with reciprocal crosses between parent strains, and F2 hybrid mice by crossing F1 mice with opposite parentage. F1 mice are genotypically identical. F2 mice are genotypically different but carry no DNA sequence not also present in F1 mice. I will measure DNA methylation levels in hippocampus from F1 and F2 mice both with and without developmental exposure to an environmentally relevant dose (500 ng/g) of MeHg in maternal diet. DNA methylation differences in F1 exposed vs. control mice will represent environmental effects; hypervariable DNA methylation in F1 control mice will represent stochastic effects. Genetic sequence variants that predict DNA methylation in F2 control mice will represent genetic effects; sequence variants that predict differential methylation in F2 exposed vs. control will represent gene-environment interactions. These results will provide insight into causes of inter-individual differences in MeHg neurotoxicity. Critically, this work will improve our mechanistic understanding of DNA methylation response to toxicants. ! !
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Kimberly Mcallister
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