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Obesity alters phosphoramide mustard-induced ovarian DNA repair in mice
Shanthi Ganesan1, Jackson Nteeba1, Jill A Madden1
1Department of Animal Science, Iowa State University, Ames, IA, USA.
Abstract:
Phosphoramide mustard (PM) destroys rapidly dividing cells and activates the DNA double strand break marker, γH2AX, and DNA repair in rat granulosa cells and neonatal ovaries. The effects of PM exposure on DNA damage and activation of DNA damage repair in lean and obese female mice were investigated. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice received sesame oil or PM (95%; 25 mg/kg; intraperitoneal injection). Obesity increased (P < 0.05) hepatic and spleen but decreased (P < 0.05) uterine weight. PM exposure reduced (P < 0.05) spleen weight regardless of body composition, however, decreased (P < 0.05) ovarian and hepatic weight were observed in the obese PM-exposed females. PM decreased (P < 0.05) primordial and primary follicle number in lean females. Obesity and PM increased (P < 0.05) γH2AX protein. DNA damage repair genes Prkdc, Parp1, and Rad51 mRNA were unaltered by obesity, however, Atm and Xrcc6 mRNA were increased (P < 0.05) while Brca1 was reduced (P < 0.05). Obesity reduced (P < 0.05) PRKDC, XRCC6 and but increased (P < 0.05) ATM protein. ATM, BRCA1 and RAD51 protein levels were increased (P < 0.05) by PM exposure in both lean and obese mice, while PM-induced increased (P < 0.05) XRCC6 and PARP1 were observed only in lean mice. Thus, PM induces ovarian DNA damage in vivo; obesity alters DNA repair response gene mRNA and protein level; the ovary activates DNA repair proteins in response to PM; but obesity compromises the ovarian PM response.
Insights
Phosphoramide mustard (PM) induces ovarian DNA damage in mice. Obesity alters DNA repair gene expression and compromises the ovarian response to PM, impacting reproductive health.
Area of Science:
- Reproductive Toxicology
- Molecular Biology
- Genetics
Background:
- Phosphoramide mustard (PM) is known to damage DNA and activate DNA repair pathways.
- The impact of obesity on cellular responses to genotoxic agents like PM is not fully understood.
- Investigating these effects is crucial for understanding reproductive health in diverse populations.
Purpose of the Study:
- To investigate the effects of PM exposure on DNA damage and repair in lean and obese female mice.
- To determine how obesity influences the ovarian response to PM-induced DNA damage.
- To analyze changes in DNA damage repair gene expression and protein levels.
Main Methods:
- Comparison of lean and obese mice exposed to PM or vehicle control.
- Assessment of organ weights (liver, spleen, uterus, ovary).
- Analysis of DNA damage marker γH2AX, and mRNA/protein levels of DNA repair genes (Prkdc, Parp1, Rad51, Atm, Xrcc6, Brca1).
Main Results:
- PM exposure decreased ovarian weight and follicle numbers in lean mice.
- Both obesity and PM increased γH2AX protein levels, indicating DNA damage.
- Obesity altered mRNA and protein levels of DNA repair genes, while PM increased specific DNA repair proteins, with variations between lean and obese mice.
Conclusions:
- PM induces ovarian DNA damage in vivo.
- Obesity alters the expression of DNA repair genes and compromises the ovarian response to PM.
- These findings highlight potential risks to reproductive health associated with genotoxic exposures in obese individuals.
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