Obesity alters phosphoramide mustard-induced ovarian DNA repair in mice†

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.

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

“…In response to PM exposure in WT mice, both primordial and small primary follicle numbers were reduced in WT mice, consistent with our previous findings [26,27]. Different numbers of growing follicles post-PM treatment were not observed, suggesting lack of hyperactivation of the ovarian reserve.…”

“…Phosphoramide mustard (PM), an ovotoxic metabolite of CPA [21,22], destroys rapidly dividing cells by inducing DNA double strand breaks (DSB) [23]. The reproductive effects of PM exposure have been well characterized by our group and others, which include loss of primordial and primary follicles in mice [24][25][26][27], antral follicles in rats [28], and amenorrhea, premature ovarian failure, and infertility in women and young girls [29]. In addition to fertility issues, CPA exposure has been associated with congenital malformations in offspring exposed to CPA in utero as well as pregestational germ cell exposures [30].…”

Ovarian Follicle Depletion Induced by Chemotherapy and the Investigational Stages of Potential Fertility-Protective Treatments—A Review

“…Obesity seems to compromise the DNA repair response by altering DNA repair response-related mRNA and protein expression [146]. Researchers found that progressive obesity in mice could alter the mRNA expression of genes involved in ovarian insulin-mediated PI3K signaling, e.g.…”

Obesity alters the ovarian proteomic response to zearalenone exposure

“…Synthesis and metabolism of ovarian steroid hormones are also altered by obesity [ 50 ]. Our previous studies discovered that obesity can induce low level DNA damage [ 51 , 52 ], accelerate oxidative DNA damage and oxidative stress [ 51 ], alter the phosphatidylinositol-3 kinase (PI3K) [ 53 , 54 ] pathway, reduce and blunt the response of ovarian chemical metabolism proteins [ 53 , 55 ] and reduce primordial follicle number [ 51 , 55 , 56 ]. Thus, the ovary from an obese female has apparent greater sensitivity to reproductive toxicants.…”