Essential role of Nrf2 in protection against ovarian follicle loss induced by 4-vinylcyclohexene and 4-vinylcyclohexene diepoxide in mice.
Hu-X; Roberts-J; Kan-YW; Ma-Q
FASEB J 2004 May; 18(8):C303-C304
VCH and its metabolite VCD represent a potential health hazard, because they selectively destory 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 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 and GST. 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 background) 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. Currently, the phase II enzyme related mechanism is being investigated in ovaries with immuno-histo-chemistry and other approaches. Taken together, the findings suggest that loss of Nrf2 function and Nrf2-mediated expression of phase II genes may play an important role in detoxification of VCH and VCD, thereby protecting ovarian follicles from the ovotoxicity of the chemicals.
Laboratory-animals; Animals; Animal-studies; Health-hazards; Laboratory-testing; Genes; Enzymes
NIOSH/HELD/CDC, 1095 Willowdale Road, Morgantown, WV 26505
Conference/Symposia Proceedings; Abstract
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