The broad goal of this proposed research is to investigate the role of genetic mechanisms in regulating the extent of epigenetic defects caused by toxicant exposure. Understanding these mechanisms and how they influence susceptibility to diseases related to the environment has great potential to have a major impact on human health and disease outcomes. Specifically, this study will examine whether genetic sequence differences between individuals determines the extent and heritability of epigenetic perturbation induced by the endocrine disrupting compound (EDC) vinclozolin. Vinclozolin is an antiandrogenic fungicide at the top of a growing list of EDCs that cause epigenetic defects. Because of this link to epigenetic changes and widespread presence of EDCs in the environment, EDCs are under increasing scrutiny for a greater role in disease. Most current studies focus on identifying the epigenetic effects of EDCs including genes affected and effects on gene expression. To date, very little is known at the mechanistic level regarding the direct mode of action of epigenetic perturbation by EDCs and factors that contribute to susceptibility and heritability of EDC-induced epigenetic defects. Heritability of EDC-induced epigenetic defects highlights the potential for EDC exposure to affect health beyond initial exposure into future generations. This has great implications on future prevalence and diagnostic capabilities of EDC-related disease. Here, we propose to investigate the role of genetic sequences in cis, at the site of perturbed methylation, and in trans, outside of the site of perturbed methylation as potential genetic modifiers of epigenetic response to environment. We will primarily assay vinclozolin- induced epigenetic defects during the critical susceptibility window of germ cell development when genome- wide epigenetic reprogramming is occurring. Epigenetic defects occurring in germ cells are a likely source of germ line transmission (heritability) of environmentally-induced epimutations. We focus on epigenetic defects induced at the imprinted H19/Igf2 locus. This locus is an excellent model of epigenetic regulation due to its consistent and stably inherited epigenetic states with little variation in DNA methylation levels between cell types and individuals; the direct correlation between epigenetic state at the locus and gene expression such that changes in epigenetic state always result in gene expression changes; and the link between disruption of normal epigenetic states at this locus and diseases such as growth defects and cancers. Furthermore, genetic mutations found at the site of epigenetic defects at the H19/Igf2 locus were recently linked to heritability of the defects and manifestation of the associated human imprinting disorder. Here, we test the hypothesis that genetic sequence differences play an important role in the extent and heritability of epigenetic defects caused by EDCs. To test this hypothesis we will screen mouse models with genetic sequence differences within and outside of the known site of EDC-induced methylation defects to identify sequences that modify the epigenetic effects of EDC exposure and potentially contribute to susceptibility to EDC-related disease.

Public Health Relevance

Individuals differ greatly in health and disease outcome in response to environmental exposure. Genetic makeup is a major contributor to these individual differences and is a valuable resource in determining accurate diagnoses and preventative measures. This study aims to identify genetic differences that are responsible for determining how individuals respond to exposure to endocrine disrupting compounds (EDC), thus clarifying how DNA differences influence our susceptibility to environmentally based disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K22)
Project #
5K22ES023849-02
Application #
8970702
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Chadwick, Lisa
Project Start
2014-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Pietryk, Edward W; Clement, Kiristin; Elnagheeb, Marwa et al. (2018) Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme. Reprod Toxicol 78:9-19
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Xue, Jing; Ideraabdullah, Folami Y (2016) An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation. J Nutr Biochem 30:1-13
Xue, Jing; Schoenrock, Sarah A; Valdar, William et al. (2016) Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clin Epigenetics 8:107