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Molecular and Cellular Biology, February 2006, p. 940-954, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.940-954.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

Xiaoming Hu,1,{dagger} Jenny R. Roberts,2 Patrick L. Apopa,1,3 Yuet Wai Kan,4 and Qiang Ma1*

Receptor Biology Laboratory, Toxicology and Molecular Biology Branch,1 Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention,2 Department of Biochemistry and Molecular Pharmacology, West Virginia University, Morgantown, West Virginia,3 Department of Laboratory Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California4

Received 27 May 2005/ Returned for modification 22 July 2005/ Accepted 11 November 2005

Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2–/– female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is shown to selectively destroy small ovarian follicles, resulting in early depletion of functional follicles. Treatment with VCD induces apoptotic death in cultured cells and in ovarian follicles, suggesting apoptosis as a mechanism of follicle loss. Loss of Nrf2 function blocks the basal and inducible expression of microsomal epoxide hydrolase, a key enzyme in the detoxification of VCD, and increases the oxidative stress in cells that is further exacerbated by VCD. Foxo3a, a repressor in the early stages of follicle activation, displays reduced expression in Nrf2–/– ovaries, causing accelerated growth of follicles in the absence of exposure to exogenous chemicals. Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization. This study demonstrates that Nrf2 serves as an essential sensor and regulator of chemical homeostasis in ovarian cells, protecting the cells from toxic chemicals by controlling metabolic detoxification, reactive oxygen species defense, and Foxo3a expression. In addition, these findings raise the possibility that exposure to environmental or occupational ovotoxicants plays a role in the premature ovarian failure commonly associated with infertility and premature aging in women.

* Corresponding author. Mailing address: Receptor Biology Laboratory, TMBB/HELD/NIOSH/CDC, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505. Phone: (304) 285-6241. Fax: (304) 285-5708. E-mail: qam1{at}cdc.gov.

{dagger} Present address: Abbott Laboratories, Abbott Park, IL 60064-6122.

Molecular and Cellular Biology, February 2006, p. 940-954, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.940-954.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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