The mechanism of action of 4-vinylcyclohexene diepoxide in the induction of ovarian toxicity.

Abstract

Exposure of females to environmental chemicals can disrupt reproductive function by altering the normal functions of the oviducts, uterus, cervix, hypothalamus, anterior pituitary, or ovary. Compounds that directly affect the ovary can have a profound impact on fertility. Chemicals which destroy oocytes contained in primordial follicles cause early menopause and permanent infertility because only a finite number of these oocytes is contained within the ovary at birth and cannot be replaced. 4-vinylcyclohexene diepoxide (VCD) is one compound that has been shown to destroy oocytes contained in primordial follicles in rats and mice. The purpose of this dissertation was to determine: (1) the contribution of ovarian metabolism to VCD-induced oocyte depletion, (2) whether age is an important factor in the ability of VCD to disrupt reproduction, (3) the initial follicular and cellular target for destruction of oocytes by VCD, and (4) a possible mechanism by which VCD induces ovotoxicity. Data from this dissertation have shown that ovarian metabolism contributes to VCD-induced ovotoxicity because small pre-antral follicles (those follicles which are susceptible to VCD) were shown to have a reduced capacity to detoxify VCD compared to nontarget tissues such as large pre-antral follicles and hepatocytes. It has also been shown that age may not be an important factor in the ability of VCD to destroy oocytes because VCD destroyed oocytes to an equal extent in adult and immature rats. Age, however, was a factor in the ability of VCD to disrupt cyclicity and uterine function since reduced cyclicity and uterine weights were observed in adult, but not immature rats. Additionally, these studies have shown that the initial follicular target for VCD is the primordial follicle, 7-15 days of daily dosing are required to observe oocyte destruction, and VCD modulates secretion of a factor by granulosa cells that may lead to destruction of oocytes via inhibition of protein synthesis. Collectively, these studies have enhanced our understanding of factors which contribute to destruction of oocytes in small pre-antral follicles. Additionally, these studies have provided information regarding interactions of granulosa cells and oocytes contained in those follicles.