Childhood obesity rates have more than tripled over the last 40 years with 18.5% of children and adolescents who are now obese. Endocrine-disrupting chemicals, particularly obesogens such as polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PFAS), are contributing to the rapid increases in obesity. Recent studies indicate that prenatal exposures to PCBs and PFAS contribute to gender-specific obesity development in children. Both groups of contaminants share a common underlying mechanistic pathway, that of oxidative stress, and their actions arise from the considerable crosstalk between transcription factors including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the aryl hydrocarbon receptor. Others have found that treating cells in culture directly with PCBs or PFAS [perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA)] influences adipogenesis using human and mouse cells. Importantly, PFOS induced adipogenesis and glucose uptake by acting through Nrf2. Using a mouse model as part of the previous round of funding, similar observations were made in that offspring exposed perinatally to PCBs had significantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Further, mature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring from vehicle-treated dams. Importantly, a healthy behavioral intervention, maternal voluntary exercise during pregnancy, improved offspring disease risk associated with in utero PCB exposure. The proposed project will continue to use an in vivo mouse model as well as transition to human samples in order to examine the molecular impact of environmental contaminant toxicity during a narrow window of susceptibility.
Aim 1 will test whether voluntary exercise during pregnancy or in the offspring themselves can be used as an intervention strategy to protect against the long-term metabolic detriments associated with in utero PCB exposure.
Aim 2 will elucidate the mechanism of impaired glucose tolerance and altered body composition in offspring born to PCB-exposed dams (including the use of Nrf2 knockout mice), and will determine how maternal exercise is protecting offspring from these impairments.
Aim 3 will use human cells to identify biomarkers of the specific harm associated with in utero halogenated organic pollutant exposures and to elucidate the potential mechanisms that contribute to increased obesity and diabetes risk in exposed infants. Our work will measure actual contaminant exposure levels in maternal and cord serum, and quantify adipocyte differentiation directly in cells isolated from the same neonates. Anticipated results are particularly significant in that they highlight early developmental stages as potential periods of particular vulnerability to program lasting obesity and diabetes effects of toxic environmental insults.

Public Health Relevance

Obesity and diabetes are at epidemic levels, and the toxicity of environmental contaminants during perinatal development could be a significant contributor to these trends. The proposed studies will offer innovative new insights to understanding the role of exercise in mitigating the health impacts of in utero contaminant exposures. Project 2 clearly addresses three of the Superfund Research Program primary objectives: Mandate 1, ?advanced techniques for detection, assessment and evaluation of the effect of hazardous substances on human health?, Mandate 2, ?methods to assess the risks to human health presented by hazardous substances?, and Mandate 4, ?methods to reduce the amount and toxicity of hazardous substances.?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES007380-22
Application #
9841181
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
22
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
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