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Pre-pubertal obesity compromises ovarian oxidative stress, DNA repair and chemical biotransformation
Kelsey Timme1, M Estefanía González-Alvarez1, Aileen F Keating1
1Department of Animal Science, Iowa State University, Ames, IA, USA.
Abstract:
Obesity in adult females impairs fertility by altering oxidative stress, DNA repair and chemical biotransformation. Whether prepubertal obesity results in similar ovarian impacts is under-explored. The objective of this study was to induce obesity in prepubertal female mice and assess puberty onset, follicle number, and abundance of oxidative stress, DNA repair and chemical biotransformation proteins basally and in response to 7,12-dimethylbenz(a)anthracene (DMBA) exposure. DMBA is a polycyclic aromatic hydrocarbon that has been shown to be ovotoxic. Lactating dams (C57BL6J) were fed either a normal rodent containing 3.5% kCal from fat (lean), or a high fat diet comprised of 60% kCal from fat, and 9% kCal from sucrose. The offspring were weaned onto the diet of their dam and exposed at postnatal day 35 to either corn oil or DMBA (1 mg/kg) for 7 d via intraperitoneal injection. Mice on the HFD had reduced (P < 0.05) age at puberty onset as measured by vaginal opening but DMBA did not impact puberty onset. Heart, spleen, kidney, uterus and ovary weight were increased (P < 0.05) by obesity and liver weight was increased (P < 0.05) by DMBA exposure in obese mice. Follicle number was largely unaffected by obesity or DMBA exposure, with the exception of primary follicle number, which were higher (P < 0.05) in lean DMBA exposed and obese control relative to lean control mice. There were also greater numbers (P < 0.05) of corpora lutea in obese relative to lean mice. In lean mice, DMBA exposure reduced (P < 0.05) the level of CYP2E1, EPHX1, GSTP1, BRCA1, and CAT but this DMBA-induced reduction was absent in obese mice. Basally, obesity reduced (P < 0.05) the abundance of CYP2E1, EPHX1, GSTP1, BRCA1, SOD1 and CAT. There was greater (P < 0.05) fibrotic staining in obese DMBA-exposed ovaries and PPP2CA was decreased (P < 0.05) in growing follicles by both obesity and DMBA exposure. Thus, prepubertal obesity alters the capacity of the ovary to respond to DNA damage, ovotoxicant exposure and oxidative stress.
Insights
Prepubertal obesity in female mice accelerates puberty onset and alters ovarian protein levels. Obesity impairs the ovary's ability to respond to DNA damage and ovotoxicant exposure.
Area of Science:
- Reproductive biology
- Endocrinology
- Toxicology
Background:
- Adult female obesity negatively impacts fertility by affecting oxidative stress, DNA repair, and chemical biotransformation.
- The effects of prepubertal obesity on ovarian function remain largely unexplored.
Purpose of the Study:
- To investigate the impact of prepubertal obesity on puberty onset, ovarian follicle count, and the levels of proteins involved in oxidative stress, DNA repair, and chemical biotransformation.
- To assess how obesity influences the ovarian response to 7,12-dimethylbenz(a)anthracene (DMBA), an ovotoxic polycyclic aromatic hydrocarbon.
Main Methods:
- Obesity was induced in prepubertal female mice (C57BL6J) using a high-fat diet (HFD) from lactation.
- Offspring were exposed to either corn oil or DMBA at postnatal day 35.
- Puberty onset (vaginal opening), organ weights, follicle numbers, corpora lutea, and protein/fibrotic staining in ovaries were analyzed.
Main Results:
- Mice on the HFD exhibited earlier puberty onset but DMBA did not affect puberty timing.
- Obesity increased the weight of several organs, including the ovaries, while DMBA exposure increased liver weight in obese mice.
- While overall follicle numbers were mostly unaffected, primary follicle numbers were higher in lean DMBA-exposed mice and obese controls.
- Obesity reduced basal levels of key proteins (CYP2E1, EPHX1, GSTP1, BRCA1, SOD1, CAT).
- DMBA exposure reduced these protein levels in lean mice, but this effect was absent in obese mice, suggesting altered ovotoxicant response.
- Obese DMBA-exposed ovaries showed increased fibrotic staining, and PPP2CA levels decreased in growing follicles due to both obesity and DMBA exposure.
Conclusions:
- Prepubertal obesity accelerates puberty onset and alters ovarian protein expression related to oxidative stress and DNA repair.
- Obese prepubertal mice exhibit an impaired ovarian response to DNA damage and ovotoxicant exposure, potentially affecting long-term fertility.
- These findings highlight the critical impact of early-life nutrition on reproductive health and ovarian resilience.
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