Ovarian Toxicity of 4-Vinylcyclohexene Diepoxide: A Mechanistic Model

Abstract

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.

Rictor/mTORC2 Pathway in Oocytes Regulates Folliculogenesis, and Its Inactivation Causes Premature Ovarian Failure

“…However, the roles of Rictor/mTORC2 in folliculogenesis are currently unknown. In this study, we demonstrated that Rictor activity and downstream mTORC2 signaling are suppressed in ovaries treated with the ovotoxicant, 4-vinylcyclohexene diepoxide (VCD), an occupational chemical shown to cause POF in human and animal models by accelerating the apoptotic process of atresia (23)(24)(25)(26)(27). Additionally, induction of oocyte-specific ablation of Rictor with the Cre-loxp system using Zp3-Cre and Rictor loxp/loxp mice resulted in POF phenotypes.…”

Fertility control to mitigate human–wildlife conflicts: a review

“…The epoxide 4-vinylcyclohexene diepoxide (VCD) has ovarian-specific toxicity and follicle-depleting properties (Hoyer et al 2001;Mayer et al 2002). The administration of VCD by injection or ingestion repeatedly over a period of up to 30 days depletes the ovary of follicles leading to ovarian senescence (Mayer et al 2004;Hu et al 2006).…”

All Your Eggs in One Basket: Mechanisms of Xenobiotic Induced Female Reproductive Senescence

“…There is now an increasing volume of studies which link primordial follicle depletion with xenobiotic exposure, suggesting that these irreplaceable follicles are highly sensitive to www.intechopen.com cytotoxic insult (Hoyer and Devine, 2001;Mattison et al, 1983aMattison et al, , 1983bSobinoff et al, 2010Sobinoff et al, , 2011. It is thought that this sensitivity may stem from the primordial follicles quiescent nature.…”

“…The use of ovotoxic xenobiotics as agents of contraception/sterilisation represents a novel approach to fertility control. Of particular interest are xenobiotics which have been shown to cause POF by specifically targeting the primordial follicle population for degradation (Hoyer and Devine, 2001;Sobinoff et al, 2010), thus causing permanent sterility.…”

“…There is now a growing body of evidence which suggests that foreign synthetic chemicals, also known as xenobiotics, are capable of causing POF by inducing premature follicular depletion. Indeed, exposure to pesticides, workplace chemicals, chemotherapeutic agents and cigarette smoke have all been associated with primordial follicle reduction resulting in premature ovarian senescence (Hoyer and Devine, 2001;Mattison et al, 1983aMattison et al, , 1983bSobinoff et al, 2010Sobinoff et al, , 2011.…”