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17ß-Estradiol Affords Protection against 4-Vinylcyclohexene Diepoxide-Induced Ovarian Follicle Loss in Fischer-344 Rats

Departments of Physiology (K.E.T., P.B.H.) and Pharmacology and Toxicology (I.G.S.), Southwest Environmental Health Sciences Center (I.G.S., P.B.H.), and Arthritis Center (B.D.G.), University of Arizona, Tucson, Arizona 85724

Address all correspondence and requests for reprints to: Dr. Patricia B. Hoyer, Department of Physiology, University of Arizona, 1501 North Campbell Avenue, Tucson, Arizona 85724-5051. E-mail: . hoyer{at}u.arizona.edu

Repeated dosing with 4-vinylcyclohexene diepoxide (VCD) accelerates atresia via apoptosis in primordial and primary follicles in ovaries of rats. The mechanisms that control atresia and VCD-induced toxicity are unknown; however, they could involve 17ß-E2. Atresia slows as animals enter puberty, whereas circulating E2 levels increase with the the onset of cyclicity. This inverse relationship suggests that E2 may be involved in the control of atresia. Therefore, this study was designed to determine whether treatment of immature rats with E2 could protect follicles normally destroyed by VCD-induced apoptosis. Female F344 rats were treated daily with E2, ER analogs, and/or VCD for 15 d. VCD alone caused a 50% reduction in primordial and primary follicles. Coinjection of E2 (0.1 mg/kg) and VCD (80 mg/kg) selectively protected primary follicles from VCD-induced follicle loss. This protection was mimicked by an ER agonist, genistein (0.1 mg/kg), and prevented by an ER antagonist, 4-hydroxytamoxifen (2 mg/kg). VCD treatment increased caspase-3-like activity, whereas concurrent treatment with genistein and VCD restored caspase-3-like activity to control levels. VCD treatment had no effect on circulating E2 levels, uterine weight, or E2 binding to the ER, nor could it directly displace E2 from ERß. These observations support the idea that ER-mediated protection against VCD-induced follicle toxicity is obtained by reducing apoptosis in small preantral follicles, although VCD does not appear to directly interact with ER.

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