Environmental Epigenetics of EDCs: From Germline to Brain

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ABSTRACT Exposures to environmental endocrine-disrupting chemicals (EDCs), especially during early life, are strongly linked to adverse health outcomes including neurobehavioral, reproductive, and other endocrine dysfunctions. EDC exposures to a fetus (F1) also exposes the germline and causes heritable epigenetic changes that are passed to future generations. There are a number of limitations to prior work that I will overcome in the current RIVER application. Most EDC research is limited to a single tissue type or a single mechanism with a limited number of targets. This is particularly complicated in the brain because of its heterogeneity. The field is also limited by a surprisingly small number of studies that compare sex differences, yet EDCs have profoundly different effects on the developing male and female brain, body, and germline, which are subject to sex-specific epigenetic programming and therefore sex-specific phenotypes. Finally, how epigenetic programming propagates from gamete to somatic cells and causes tissue-specific diseases such as neurobehavioral disorders is a fundamental question, one that (to my knowledge) has never been addressed. This RIVER application has three overarching areas of inquiry. 1) What are the epigenetic mechanisms by which environmental EDCs organize brain development at the cellular level, and lead to functional neurobiological deficits in exposed individuals? 2) Which epigenetic mechanism(s) is responsible for programming of the germline to enable transmission across generations? 3) How does epigenetic programming in the germline manifest as cell-specific phenotypes in somatic cells (e.g. brain)? To address these questions we will use our established rat EDC exposure model with human-relevant chemicals, dosages, and route, in which direct (F1), intergenerational (F2), and multigenerational (F3) work will be performed in both the brain and the gametes. I am uniquely qualified to lead this research program as an environmental neuroendocrinologist doing groundbreaking multigenerational epigenetic work. We will do single-cell multiomic profiling of both the brain and gametes at the RNA, DNA, and small-noncoding RNA (sncRNA) level, enabling us to pinpoint the cell types influenced by EDCs, and how phenotypes are propagated from gametes to individuals and across developmental stages. Established bioinformatic pipelines will inform on these mechanisms individually, as well as their relationships. Crucially, the lines of work in brain and gametes will be connected by relating epigenomic profiles in brain and germ cells to one another, thereby determining how epigenomic marks in gametes are reflected in the brain. These data will establish definitive epigenetic profiles that will allow us to identify the origin of EDC induced epigenetic modifications and provide potential targets for therapeutics in humans, with which the mechanisms studied in rats are highly conserved. The flexibility and security of the RIVER program is necessary to fully realize the promise of this likely paradigm-shifting research.