Date of Award
Doctor of Philosophy
Genetics and Genomics
Aileen F. Keating
The ovary is the female reproductive organ responsible for the production of both the female gamete, the oocyte, and two major female sex hormones, estradiol and progesterone. During embryonic development, oocytes are formed from primordial germ cells and eventually become surrounded by squamous granulosa cells in a follicular structure, termed primordial. The oocyte numbers encased in primordial follicles are finite at birth and remain arrested in the diplotene stage of meiosis until ovulation or they degenerate through atresia. Once the pool of primordial follicles is depleted, ovarian senescence occurs. We hypothesized that the maternal metabolic changes that occur during lean gestational diabetes mellitus would impact offspring ovarian function both basally and in response to a dietary stressor later in life. We observed impacts on follicle numbers and alterations in the ovarian proteome, suggesting possible impacts on fertility and oocyte quality in relation to in utero and metabolic stressors. Additionally, we hypothesized that the ovarian DNA damage response is altered during obesity in adulthood. An elevated response in markers of DNA damage was observed, indicating that the metabolic status of the ovary during obesity initiates a low-level DNA damage response. Intercellular communication is also affected by a metabolic syndrome such as obesity or GDM exposure, with reduction of the gap junction protein Connexin-43 expression in antral follicles from ovaries that experienced obesity. Finally, to elucidate the molecular mechanisms behind the induction of the DNA damage response in the ovary after phosphoramide mustard exposure, we hypothesized that the DNA damage response would be blunted due to reduced abundance of the ATM protein. Using an Atm+/- mouse model to investigate impacts on folliculogenesis and the ovarian proteome, we determined that Atm haploinsufficiency results in an irregular DNA damage response, alters the ovarian proteome, and impacts the rate of follicle loss after phosphoramide mustard exposure. Taken together, these findings demonstrate that the DNA damage response is initiated in the ovary during times of metabolic stress and in the absence of Atm, unhealthy follicles remain in the ovary, potentially contributing to poor oocyte quality or infertility.
Kendra Leah Clark
Clark, Kendra Leah, "Deciphering the ovarian proteomic impacts of obesity" (2019). Graduate Theses and Dissertations. 17659.
Available for download on Saturday, September 26, 2020