Impacts of obesity on ovarian chemical metabolism

The ovary is responsible for the production of steroid hormones, such as 17β-estradiol and progesterone, and the female gamete. Females are born with a finite number of oocytes enclosed in primordial follicles which are established during gestation. The ovary produces xenobiotic biotransformation proteins to protect the ovary from ovotoxicant exposure. Approximately one third of reproductive age women in the United States are obese and negative reproductive issues are associated with obesity. Obesity alters the estrous cycle, depletes primordial follicles, causes poor oocyte quality, and reduces fecundity. Glyphosate (GLY) has been used for decades as an herbicide in rural and urban settings. This thesis investigated the central hypothesis that obesity alters chemical biotransformation proteins in ways that hamper chemical biotransformation. To test this hypothesis, two animal models were employed: The first study used rats fed a control (CT) or high fat diet (HFD; 60% Kcal) from 4-22 weeks of age until the HFD-fed were ~30% heavier than the CT rats. The second study used lean mice or mice who become obese through hyperphagia. Lean and obese mice were exposed to saline or GLY (2mg/kg/d) per os daily for 10 weeks. Ovarian follicles were classified and counted; protein was analyzed via western blotting or LC-MS/MS; 17β-estradiol and progesterone were quantified via ELISA kits. Our findings demonstrated that primordial follicles were depleted in obese relative to lean rats, but that there was no impact of obesity on abundance of ovarian chemical biotransformation protein abundance in rats. Exposure to GLY did not alter 17β-estradiol, progesterone, body weight, or organ weights in mice but altered the ovarian proteome in ways that could affect the response to chemical exposure. Additionally, the proteomic response to GLY exposure differed between lean and obese mice. Taken together, this data demonstrates that obesity reduces primordial follicle number, alters the ovarian proteome, and that GLY exposure differentially affects the ovary in lean and obese mice. These findings discount that GLY disrupts ovarian steroid hormones and add to our understanding of factors important for ovarian function