. The environmental chemical, 4-Vinylcyclohexene (VCH) is produced in the manufacture of rubber tires, flame retardants, insecticides, plasticizers, and antioxidants. Dosing (30 d) with the diepoxide metabolite, 4-vinylcyclohexene diepoxide (VCD) destroys the majority of small pre-antral (primordial) follicles in the ovaries of mice and rats. Females are born with a finite number of primordial follicles that cannot be regenerated; thus, chemicals that destroy oocytes contained in these follicles can produce premature ovarian failure. As a result, exposure of women to ovotoxicants in the environment is of concern. In addition to VCH and VCD, other industrial chemicals that can form diepoxides, butadiene and isoprene, also destroy primordial follicles in mice. Whether these ovotoxicants all act by similar cellular mechanisms is unknown. Previous studies with VCD (80 mg/kg) in rats showed that destruction of small follicles requires daily dosing (10 days), is via physiological cell death (apoptosis), and is accompanied by altered expression of genes associated with apoptosis (bax). The studies proposed here will investigate the role of receptor-mediated signaling pathways that regulate VCD-induced apoptosis. Using end-points identified with VCD, other ovotoxic occupational diepoxides will also be tested in rats to determine whether these events represent a universal mechanism of follicular destruction. The hypothesis to be tested is that VCD and other ovotoxic diepoxides cause destruction of small pre-antral (primordial) ovarian follicles via common intracellular signaling pathways.
The Specific Aims are to: 1) determine whether growth factor receptors are affected in follicular apoptosis induced by VCD, 2) identify protein kinase pathways involved in VCD signaling for ovotoxicity, 3) characterize the effect of VCD on steady state gene expression in ovotoxicity, and 4) determine whether ovotoxicity induced by other chemicals is via similar mechanisms. The studies will use an integrated morphological, biochemical, and molecular approach to provide a greater understanding of ovotoxicity caused by environmental chemicals, and thus, will provide greater insight as to the impact of these specific factors on reproductive health in women.
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