title: Bisphenol A-Induced Ovotoxicity Involves DNA Damage Induction to Which the Ovary Mounts a Protective Response Indicated by Increased Expression of Proteins Involved in DNA Repair and Xenobiotic Biotransformation.
abstract: Bisphenol A (BPA) is an endocrine disrupting chemical with ubiquitous human exposure. BPA causes primordial follicle loss and DNA damage in germ cells, thus we hypothesized that BPA induces ovarian DNA damage, thereby precipitating follicle loss. We also anticipated that the ovary activates DNA repair and xenobiotic biotransformation to minimize oocyte damage and/or, activate cell death signaling to deplete follicles. Postnatal day 4 F344 rat ovaries were cultured in medium containing vehicle control (1% dimethylsulfoxide [DMSO]) ± BPA (440 µM) for 2-8 days. BPA reduced (P < 0.05) small primary, large primary and secondary follicle numbers after 2 days, followed by a reduction (P < .05) in primordial follicle numbers after 4 days. Phosphorylated H2AX (γH2AX) and Ataxia-telangiectasia mutated (ATM), markers of DNA double-strand breaks, were increased (P < .05) in abundance prior to observed follicle loss. DNA repair genes (Atm, Prkdc, Xrcc6, Brca1, Mre11a, Rad50, and Smc1a) were increased (P < .05) after 1 day of BPA exposure. mRNA encoding Meh, Gstm, c-kit, Kitlg, and Akt were increased (P < .05), as was MEH, AKT, pAKT, Jun N-terminal kinase, and P53 protein abundance, while GST isoforms pi and Nuclear factor erythroid-related factor 2 proteins were decreased (P < .05) by BPA exposure. These data demonstrate the dynamic ovarian response to BPA exposure, which indicates that BPA, via biotransformation, may be converted to a DNA alkylating agent, causing ovarian DNA damage, to which the ovary mounts a protective response and further our knowledge on the biological impacts of BPA on the female germline.
authors.affiliation: Department of Animal Science, Iowa State University, Ames, Iowa 50011.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Animal Science, Iowa State University, Ames, Iowa 50011 akeating@iastate.edu.
authors.forename: Aileen F
authors.initials: AF
authors.lastname: Keating
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000633:toxicity*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010636:Phenols / Q000378:metabolism / Q000633:toxicity*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D046509:Tissue Culture Techniques; D000098826:Bisphenol A Compounds
chemical_list: D051017:Apoptosis Regulatory Proteins; D001559:Benzhydryl Compounds; D045643:DNA Repair Enzymes; D052244:Endocrine Disruptors; D010636:Phenols; D058539:Phosphatidylinositol 3-Kinase; D012333:RNA, Messenger; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: BPA; DNA damage; DNA repair; PI3K pathway; apoptosis; detoxification