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.

Public Health Relevance

Rates of infertility are increasing at alarming rates worldwide. A key contributor to infertility everywhere, including in the US, is previous and ongoing pollution of waterways and food chains. It is now clear that sub- lethal exposure to a single toxicant can be detrimental to the human reproductive system and can span generations. The mechanistic underpinnings of the effect of toxicant exposure on infertility are unclear. Here, we seek to delineate how developmental exposure to toxins causes genetic and epigenetic changes that lead to infertility, and transmit this public health issue over several generations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES030722-01A1
Application #
9911309
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Schug, Thaddeus
Project Start
2019-12-20
Project End
2024-10-31
Budget Start
2019-12-20
Budget End
2020-10-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Wayne State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202