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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

Bisphenol A-Induced Ovotoxicity Involves DNA Damage Induction to Which the Ovary Mounts a... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

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

Ganesan, Shanthi; Keating, Aileen F.
Toxicological Sciences , Volume 152 (1): 12 – Jul 1, 2016
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References (83)

Publisher
Oxford University Press
Copyright
© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected]
ISSN
1096-6080
eISSN
1096-0929
DOI
10.1093/toxsci/kfw076
pmid
27208089
Publisher site
See Article on Publisher Site

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.

Journal

Toxicological Sciences – Oxford University Press

Published: Jul 1, 2016

Keywords: BPA; DNA damage; PI3K pathway; DNA repair; detoxification; apoptosis

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