Fem ale m ammals are born with a nite number of ovarian primordial follicles that cannot be regenerated; thus, chemicals that destroy oocytes contained in these follicles can produce prem ature ovarian failure (early menopuas e in women). Exposure of women to know n ovotoxican ts, such as contaminants in cigarette smoke, is associated with early menopause . Thus, the potential risks posed by ovotoxic chemicals is of concern. Our studies have focused on the environmental chemical 4-vinylcyclohexene (VCH), which is produced during the manufacture of rubber tires, ame retardants, insecticides, plasticizers, and antioxidants. Dosing of female rats and mice with the ovotoxic diepoxide metabolite of VCH, 4-vinylcyclohexene diepoxide (VCD), for 30 days destroye d the majority of ovarian primordial follicles. Using VCD in rats as a generalized mode l for ovotoxicity, we determined that 1) repeated daily dosing is required, 2) cell death is via apoptosis, and 3) altered expression of speci c genes is involved. An integrated approach at the morphologic, biochemical, and molecular level was used to support these conclusions. Studies in isolated rat small preantral follicles (targeted for VCD-induced ovotoxicit y) focused on the role of cell death genes, mitochondrion-associated events, and VCD metabolism. We also evaluated how this information relates to human risk for early menopause . These animal research results provide a better understand ing of the potential risk of human exposure to environmental ovarian toxicants and greater insight as to the impact of these toxicants on reproductive health in wom en.