Obesity partially potentiates dimethylbenz[a]anthracene-exposed ovotoxicity by altering the DNA damage repair response in mice†
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Published on: December 19, 2019
Jaspreet K Rishi1, Kelsey Timme1, Hunter E White1
1Department of Animal Science, Iowa State University, Ames, IA, USA.
Abstract:
Obesity adversely affects reproduction, impairing oocyte quality, fecundity, conception, and implantation. The ovotoxicant, dimethylbenz[a]anthracene, is biotransformed into a genotoxic metabolite to which the ovary responds by activating the ataxia telangiectasia mutated DNA repair pathway. Basal ovarian DNA damage coupled with a blunted response to genotoxicant exposure occurs in obese females, leading to the hypothesis that obesity potentiates ovotoxicity through ineffective DNA damage repair. Female KK.Cg-a/a (lean) and KK.Cg-Ay/J (obese) mice received corn oil or dimethylbenz[a]anthracene (1 mg/kg) at 9 weeks of age for 7 days via intraperitoneal injection (n = 10/treatment). Obesity increased liver weight (P < 0.001) and reduced (P < 0.05) primary, preantral, and corpora lutea number. In lean mice, dimethylbenz[a]anthracene exposure tended (P < 0.1) to increase proestrus duration and reduced (P = 0.07) primordial follicle number. Dimethylbenz[a]anthracene exposure decreased (P < 0.05) uterine weight and increased (P < 0.05) primary follicle number in obese mice. Total ovarian abundance of BRCA1, γH2AX, H3K4me, H4K5ac, H4K12ac, and H4K16ac (P > 0.05) was unchanged by obesity or dimethylbenz[a]anthracene exposure. Immunofluorescence staining demonstrated decreased (P < 0.05) abundance of γH2AX foci in antral follicles of obese mice. In primary follicle oocytes, BRCA1 protein was reduced (P < 0.05) by dimethylbenz[a]anthracene exposure in lean mice. Obesity also decreased (P < 0.05) BRCA1 protein in primary follicle oocytes. These findings support both a follicle stage-specific ovarian response to dimethylbenz[a]anthracene exposure and an impact of obesity on this ovarian response.
Insights
Obesity impairs female fertility by reducing ovarian DNA repair capacity. This study in mice shows obesity worsens ovotoxicity from genotoxicants, impacting follicle numbers and DNA repair proteins like BRCA1.
Area of Science:
- Reproductive Biology
- Toxicology
- Genetics
Background:
- Obesity negatively impacts female reproductive functions, including oocyte quality and conception.
- The ovary activates DNA repair pathways, like ataxia telangiectasia mutated (ATM), in response to genotoxic ovotoxicants.
- Obese females exhibit basal ovarian DNA damage and a diminished response to genotoxic agents, suggesting impaired DNA repair.
Purpose of the Study:
- To investigate the hypothesis that obesity potentiates ovotoxicity through ineffective DNA damage repair.
- To examine the effects of obesity and dimethylbenz[a]anthracene exposure on ovarian function and DNA repair in mice.
Main Methods:
- Female KK.Cg-a/a (lean) and KK.Cg-Ay/J (obese) mice were administered corn oil or dimethylbenz[a]anthracene (DMBA) via intraperitoneal injection.
- Ovarian follicle counts, liver weight, uterine weight, and protein abundance of DNA repair markers (BRCA1, γH2AX) were assessed.
- Immunofluorescence staining was used to evaluate DNA damage foci (γH2AX) in ovarian follicles.
Main Results:
- Obesity increased liver weight and reduced primary, preantral, and corpora lutea counts.
- DMBA exposure affected follicle numbers and estrous cycles differently in lean and obese mice.
- Obesity reduced γH2AX foci in antral follicles and BRCA1 protein in primary follicle oocytes, indicating impaired DNA repair.
Conclusions:
- Obesity exacerbates ovotoxicity induced by genotoxicants, likely due to compromised ovarian DNA repair mechanisms.
- The findings highlight a follicle stage-specific ovarian response to DMBA and the significant impact of obesity on this response.
- Impaired DNA repair, particularly reduced BRCA1, in oocytes of obese mice contributes to reproductive dysfunction.
