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
Drug Metab Rev 2004 Aug; 36(Suppl 1):177
Occupational chemicals 4-Vinylcyclohexene (VCH) and 4-vinylcyclohexene diepoxide (VCD) selectively destroy oocytes in small pre-antral follicles leading to premature ovarian failure in animals. Metabolism of VCH and VCD by phase I and phase II enzymes plays important roles in the ovotoxicity. Nrf2 is a member of the CNC bZip family of transcription factors that mediates the basal expression and induction of phase II genes such as Nqo1 and Gst. We examined the role of Nrf2-regulated gene expression in the ovotoxicity of VCH and VCD by using Nrf2 knockout mice. Immature (28 days old) female wild-type and Nrf2 -/- mice 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. Primordial and primary follicle numbers in ovaries from wild type mice decreased significantly (p < 0.05) by either VCH or VCD. However, the follicles in ovaries from Nrf2 -/- mice exhibit much higher sensitive to the toxicity of VCH and VCD than those of wild type. Together, these results demonstrate that loss of Nrf2 function is associated with increased sensitivity to toxicity of VCH and VCD on ovary follicular development. Currently, phase II enzyme-related mechanisms are being investigated in ovaries for increased sensitivity to ovarian toxicity of VCH and VCD.
Laboratory-animals; Animals; Animal-studies; Health-hazards; Laboratory-testing; Genes; Enzymes
NIOSH/HELD/CDC, 1095 Willowdale Road, Morgantown, WV 26505
Conference/Symposia Proceedings; Abstract
Drug Metabolism Reviews