Understanding the effects of obesity on DNA damage response during DMBA-induced ovotoxicity
Date
2024-08
Authors
Rishi, Jaspreet Kaur
Major Professor
Advisor
Keating, Aileen F
Tuteja, Geetu
Essner, Jeffery
Kerns, Karl
Ross, Jason
Committee Member
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Abstract
The ovary plays a central role in the healthy reproductive function of a mammalian female. It is responsible for the production of oocytes and secretion of hormones. The normal function of the ovary can be altered by environmental exposures and the metabolic status of the female can dictate the ability of the ovary to respond to xenobiotic exposures.
The research described in this dissertation investigated the combined impacts of the environmental genotoxicant, 7,12-dimethlbenz[a]anthracene (DMBA), and obesity on the ovarian protective DNA damage response (DDR) in mice.
Chapter 2 investigated the acute ovarian response to DMBA-induced DSBs in vivo and the influence of obesity thereon. The hypothesis tested was that obesity potentiates ovotoxicity through ineffective DNA damage repair. Findings from this study suggest a follicle stage-specific ovarian response to DMBA exposure, which is blunted by obesity.
Chapter 3 investigated the hypothesis that DMBA-induced ovotoxicity alters the ovarian proteome, explicitly affecting the abundance of histones and histone variants, and that this response would vary due to obesity. Data from this study indicate a role for initiation of DDR by the histone variant, H3.3, in lean mice, regulated by RBB7, which is lagging in obese mice.
In Chapter 4, the role of the post translational modification, SUMOylation was explored during DMBA exposure in lean and obese mice. Increased levels of all SUMO isoforms and a higher level of basal SUMO-ome was discovered in the obese mice. Specific SUMO targets were also identified in both lean and obese mice during DMBA exposure.
The objective for chapter 5 was to test whether the acute effects of DMBA observed in the previous studies would cease immediately post-exposure or persist and, in obese mice, a trajectory of continued follicle loss after the cessation of DMBA exposure was discovered, which is not the case in lean mice.
Finally, in Chapter 6, the ovarian role of the DDR mediator, ataxia telangiectasia mutated (ATM) was studied. The hypothesis tested was that inhibiting ATM during DMBA exposure would enhance DMBA-induced ovotoxicity and conversely, ATM activation will enhance the DDR and ameliorate DMBA-induced ovotoxicity. Proteomic analysis detected increased DDR in the ATM-activated ovaries exposed to DMBA as compared to ATM-inhibited ovaries exposed to DMBA. Additionally, classifying the DDR into specific pathways revealed that homologous recombination is selectively preferred over non homologous end joining in ovarian ATM-mediated DDR. Specific ovarian ATM targets were also identified.
Taken together, these findings illustrate both molecular and post-translational mechanisms by which obesity influences the ovarian response to the ovotoxicant, DMBA, and demonstrate that in obese mice, detrimental effects on follicular composition are observed even after removal of the genotoxic insult.
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dissertation