Development of an animal model for ovotoxicity using 4-vinylcyclohexene: A case study

BACKGROUND The occupational chemical 4-vinylcyclohexene (VCH) has been shown to cause destruction of small pre-antral follicles in ovaries of mice. Further, its monoepoxide metabolites, 1,2-VCH epoxide, 7,8-VCH epoxide, and the diepoxide, VCD, have been shown to cause pre-antral follicle loss in rats as well as mice. Chemicals that destroy small pre-antral follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). METHODS Studies working with these chemicals over the past decade have determined a number of aspects of the mechanism(s) of small pre-antral destruction, and a variety of questions have been answered. RESULTS Specifically, it has been determined that the diepoxide (VCD) is the bioactive form and it directly targets the ovary in mice and rats. Mice are more susceptible to VCH than rats because they are capable of its metabolic bioactivation. Follicle destruction by VCD is selective for primordial and primary follicles. Mechanistic studies in rats have determined that VCD causes ovotoxicity by accelerating the natural process of atresia (apoptosis) and this requires repeated exposures. Pro-apoptotic signaling events in the Bcl-2 and mitogen activated protein kinase families have been shown to be selectively activated in fractions of small pre-antral follicles (targets for VCD). Finally, a whole ovarian culture system using neonatal mouse and rat ovaries has been developed to expand the potential for more in depth investigations into ovotoxicity caused by VCD. CONCLUSIONS This article provides an overview of the questions asked and the approaches taken in studying VCH and VCD to support these conclusions. Birth Defects Res (Part B) 80:113-125, 2007. (c) 2007 Wiley-Liss, Inc.