Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals

PROJECT SUMMARY
A single toxicant exposure during development can produce reproductive defects in adulthood and subsequent
generations, presenting a major hurdle in the prevention and treatment of human infertility. Despite its
significance, however, the mechanisms that mediate this process are poorly understood. Endocrine disrupting
chemicals (EDCs) play a role in the increasing incidence of male infertility worldwide, and mounting evidence
suggests that EDC exposure can alter gene expression and the epigenome. Our long-term goal is to determine
how environmental toxicants interfere with reproductive health so that evidence-based strategies to prevent
and treat adult-onset and transgenerational disease can be developed.!The overall objective for this NIEHS
R01 Award (PA-19-056) application is to determine genome function alterations and epigenetic regulation of
environmentally-influenced infertility. The central hypothesis is that sublethal EDC exposure during male gonad
development leads to genomic and epigenetic dysregulation that alters testicular mitochondrial function in
exposed generation and subsequent generations. The rationale for the proposed research is that investigation
of the mechanisms underlying EDC induced infertility will advance prevention, risk-assessment, diagnostic,
and treatment strategies for human male infertility. Guided by strong preliminary data, this hypothesis will be
tested by pursuing three specific aims: 1) Determine testicular cell-type specific and life stage specific changes
in genome function to identify critical windows for biomarkers of effect and gene relationships; 2) Identify
changes in the epigenome related to phenotypic and genetic endpoints; 3) Determine multigenerational and
transgenerational cell-specific transcriptomic and epigenetic changes induced by ancestral exposure.
Ultimately, these results will identify critical windows for biomarkers of effect, inform the interplay among
pathways mediating toxic endpoints.

Grant Number: 5R01ES030722-05
NIH Institute/Center: NIH
Principal Investigator: Tracie Baker