THE GESTATION OF HEALTH: ENVIRONMENTAL INSULTS, BEHAVIORAL INTERVENTIONS, AND PROTECTIVE MECHANISMS
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Doctor of Philosophy (PhD)
Pharmacology and Nutritional Sciences
Dr. Kevin Pearson
Diabetes remains a leading cause of death nationwide despite pharmacological advances. Recent etiological investigations of the disease detail the role of perinatal exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), in enhancing disease susceptibility. Polychlorinated biphenyl 126, a coplanar PCB, elicits its toxic effects through the aryl-hydrocarbon receptor and the disruption of endocrine signaling. The goal of this dissertation was to focus on delineating the differences in the developmental windows of diabetes susceptibility respective to the timing of PCB126 exposure and to understand the influence of maternal exercise and nuclear-factor erythroid-2-related factor 2 (Nrf2) expression in combating the negative effects of PCB126 on diabetes development and progression in offspring. We found that exposure to PCB126 during the nursing period caused significant but short-term impairments in glucose tolerance with no detrimental effects on offspring body weight or composition (Aim 1), whereas exposure to PCB126 during the gestational period results in long-term adverse alterations in offspring glucose homeostasis and body weight and composition. Additionally, our analyses revealed that voluntary maternal exercise attenuated fat deposition and improved glucose disposal in adult male offspring perinatally exposed to PCB126 (Aim 2). Further, we discovered that offspring phenotypic and metabolic response to PCB126 is modulated by maternal, but not offspring, Nrf2 expression (Aim 3). Taken together, these data affirm the in utero period is the critical window of PCB exposure resulting in long-term negative developmental programming effects, indicate the potential of voluntary perinatal maternal exercise as a therapeutic intervention against the harmful effects of PCB126, and establish the extent to which Nrf2 expression influences PCB-induced perturbations in redox homeostasis throughout the lifecycle. Future studies will investigate the mechanisms of dysfunction caused by in utero PCB126 exposure while exploring the influence of maternal behavior and nutrition on offspring health.
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Funding for my dissertation research was generously provided by the National Institute of Environmental Health Sciences (P42ES007380) and the National Institute of General Medical Sciences (P20GM103527) in 2016 - 2021.
Rice, Brittany Breon, "THE GESTATION OF HEALTH: ENVIRONMENTAL INSULTS, BEHAVIORAL INTERVENTIONS, AND PROTECTIVE MECHANISMS" (2021). Theses and Dissertations--Pharmacology and Nutritional Sciences. 39.
Available for download on Friday, September 29, 2023