4-Vinylcyclohexene (VCH), an industrial chemical, and its metabolite 4-vinylcy-clohexene diepoxide (VCD), represent a potential health hazard, because they selectively destroy oocytes in small pre-antral follicles leading to premature ovarian failure in animals. Previous studies suggest that metabolism of VCH and VCD by phase I and phase II drug-metabolism enzymes plays an important role in the ovotoxicity of these chemicals. Nrf2 is a member of the Cap "N" Colar bZip family of transcription factors that mediates the basal expression and induction of phase II enzymes such as NQO1. In this study, we examined the role of Nrf2-regulated gene expression in the ovotoxicity of VCH and VCD by using Nrf2 knockout mice. Immature (age, day 28) female wild-type and Nrf2-/- mice (both in B6 back-ground) were treated with VCH or VCD using established protocols; 4 h following the final dose, ovaries were collected. Complete serial sections of ovaries were evaluated histologically for the presence of follicles. As expected, the primordial and primary follicle numbers in ovaries from wild type mice decreased significantly (p<0.05) following treatment with either VCH or VCD. However, the primordial and primary follicles in ovaries from Nrf2-/- mice exhibit much higher sensitive to the toxicity of VCH and VCD than those of wild type mice. Both VCH and VCD have no significant effects on growing or pre-antral follicles in either genotypes. Taken together, these results demonstrate that loss of Nrf2 function is associated with increased sensitivity to toxicity of VCH and VCD on ovary follicle development. The findings suggest that Nrf2-mediated expression of phase II genes plays an important role in detoxification of VCH and VCD, thereby protecting ovarian follicles from the ovotoxicity of the chemicals.
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland