title: 4-vinylcyclohexene diepoxide: a model chemical for ovotoxicity.
abstract: The occupational chemical 4-vinylcyclohexene diepoxide (VCD) has been shown to cause selective destruction of ovarian small pre-antral (primordial and primary) follicles in rats and mice by accelerating the natural, apoptotic process of atresia. Chemicals that destroy primordial follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). Initial studies using in vivo exposure of rats determined that VCD specifically targets primordial and primary (small pre-antral) follicles and that repeated dosing is required. Through a method of isolation of ovarian small follicles, biochemical and molecular studies determined that intracellular pro-apoptotic pathways are activated following VCD dosing in rats. Subsequently an in vitro system using cultured whole neonatal rat ovaries was developed to provide more mechanistic information. That approach was used to demonstrate that the cell survival c-kit/kit ligand signaling pathway is the direct target for VCD-induced ovotoxicity. Specifically, VCD directly interacts with the oocyte-associated c-kit receptor to inhibit its autophosphorylation, and thereby impair oocyte viability. The cellular and molecular approach developed to determine these findings is described in this article.
authors.affiliation: Department of Physiology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA. hoyer@email.arizona.edu
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Kappeler
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053138:Cyclohexenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009784:Occupational Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016273:Occupational Exposure; D006080:Ovarian Follicle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D046509:Tissue Culture Techniques; D018675:Toxicity Tests / Q000379:methods*; D014753:Vinyl Compounds / Q000633:toxicity*
chemical_list: D053138:Cyclohexenes; D004785:Environmental Pollutants; D014753:Vinyl Compounds; C012606:4-vinyl-1-cyclohexene dioxide; D019009:Proto-Oncogene Proteins c-kit