Impact of obesity on ovotoxicity induced by 7,12-dimethylbenz[a]anthracene in mice
Jackson Nteeba1, Shanthi Ganesan, Aileen F Keating
1Department of Animal Science, Iowa State University, Ames, Iowa.
Abstract:
Insulin, elevated during obesity, regulates xenobiotic biotransformation enzymes, potentially through phosphatidylinositol 3-kinase (PI3K) signaling, in extraovarian tissues. PI3K regulates oocyte viability, follicular activation, and ovarian chemical biotransformation. 7,12-Dimethylbenz[a]anthracene (DMBA), a carcinogen and ovotoxicant, destroys all stages of follicles, leading to premature ovarian failure. Obesity has been reported to promote DMBA-induced tumors, but it remains unknown whether obesity affects ovarian xenobiotic metabolism. Therefore, we investigated ovarian expression of xenobiotic metabolism genes-microsomal epoxide hydrolase (Ephx1), glutathione S-transferase (GST) class Pi (Gstp1) and class mu 1 (Gstm1), and PI3K-signaling members (protein kinase B [AKT] alpha [Akt1], beta [Akt2], and the forkhead transcription factor subfamily 3 [Foxo3])-in lean and obese female mice after DMBA exposure (1 mg/kg; intraperitoneal injection for 14 days). Relative to lean, obese mice had decreased (P < 0.05) healthy primordial and primary follicle numbers but increased (P < 0.05) secondary and preovulatory follicles numbers. Obesity increased (P < 0.05) Akt1, Akt2, Gstm1, and Ephx1 mRNA and pAKT(Ser473/Thr308), GSTM1, GSTP1, and EPHX1 protein levels. DMBA decreased (P < 0.05) ovarian weight in lean and obese mice, however, obese DMBA-treated females had a greater reduction (P < 0.05) in ovarian weight. In both lean and obese mice, DMBA decreased (P < 0.05) all stages of healthy follicle numbers, increased Gstp1 and Ephx1 mRNA as well as GSTM1, GSTP1, and EPHX1 protein levels, and decreased Akt1 and Akt2 mRNA as well as pAKT(Ser473) or pAKT(Thr308), FOXO3, and pFOXO3(Ser253) protein expression. There was an additive effect between obesity and DMBA exposure for increased Gstm1 and Ephx1 mRNA as well as GSTM1 and EPHX1 protein expression.
Insights
Obesity alters ovarian xenobiotic metabolism and follicle development. Combined obesity and carcinogen (DMBA) exposure exacerbates these effects, impacting ovarian function and potentially increasing cancer risk.
Area of Science:
- Reproductive Toxicology
- Metabolomics
- Endocrinology
Background:
- Obesity is linked to altered insulin signaling and xenobiotic metabolism in extraovarian tissues.
- Insulin and PI3K signaling pathways regulate ovarian functions, including oocyte viability and chemical biotransformation.
- The carcinogen 7,12-Dimethylbenz[a]anthracene (DMBA) is ovotoxic and can lead to premature ovarian failure.
Purpose of the Study:
- To investigate the impact of obesity on ovarian xenobiotic metabolism and gene expression.
- To examine the effects of DMBA exposure on ovarian xenobiotic metabolism in lean and obese mice.
- To determine the interplay between obesity and DMBA exposure on ovarian follicle dynamics and gene expression.
Main Methods:
- Comparative analysis of ovarian xenobiotic metabolism genes (Ephx1, Gstp1, Gstm1) and PI3K-signaling members (Akt1, Akt2, Foxo3) in lean and obese female mice.
- DMBA (1 mg/kg) administered via intraperitoneal injection for 14 days.
- Assessment of follicle numbers, ovarian weight, and gene/protein expression levels.
Main Results:
- Obesity decreased healthy primordial/primary follicles but increased secondary/preovulatory follicles.
- Obesity upregulated ovarian Akt1, Akt2, Gstm1, Ephx1 mRNA and related proteins.
- DMBA exposure reduced ovarian weight and all follicle stages, increasing xenobiotic enzyme expression and decreasing PI3K signaling markers. Obesity and DMBA had additive effects on Gstm1 and Ephx1 expression.
Conclusions:
- Obesity significantly alters ovarian xenobiotic metabolism and follicle composition.
- DMBA exposure negatively impacts ovarian health, with exacerbated effects in obese mice.
- The combined effects suggest increased susceptibility to environmental toxins and potential reproductive health risks in obese individuals.
