Abstract
Background4-vinylcyclohexene diepoxide (VCD) has long been considered a hazardous occupational chemical that promotes ovarian failure. However, VCD is also used as a research compound to chemically induce animal models of premature ovarian insufficiency (POI), and in related work we unexpectedly found that VCD apparently exhibits both dose- and duration-dependent opposing, hormone-like effects on the maintenance of the primordial follicle pool, follicle development, and ovulation induction.ResultsWe conducted experiments with cultured murine ovaries and performed transplantation experiments using postnatal day (PD) 2 and PD12 mice and found that low-dose, short-term exposure to VCD (VCDlow) actually protects the primordial/primary follicle pool and improves the functional ovarian reserve (FOR) by disrupting follicular atresia. VCDlow inhibits follicular apoptosis and regulates the Pten-PI3K-Foxo3a pathway. Short-term VCD exposure in vivo (80 mg/kg, 5 days) significantly increases the number of superovulated metaphase II oocytes, preovulatory follicles, and corpus luteum in middle-aged mice with diminished ovarian reserve (DOR). We demonstrate that low-dose but not high-dose VCD promotes aromatase levels in granulosa cells (GCs), thereby enhancing the levels of estradiol secretion.ConclusionOur study illustrates a previously unappreciated, hormone-like action for the occupational “ovotoxin” molecule VCD and strongly suggests that VCDlow should be explored for its potential utility for treating human ovarian follicular development disorders, including subfertility in perimenopausal women.
Highlights
An ovary contains a finite pool of oocyte-containing follicles at different developmental stages, and this pool of dormant primordial follicles provides developing follicles and oocytes, known as the functional ovarian reserve (FOR) over the entire female reproductive lifespan as controlled by numerous regulatory signals (Adhikari and Liu, 2009)
Allograft-paired ovaries from a single PD2 donor mouse were separately transplanted into two 2month-old ovariectomized host mice, one of which was exposed to vinylcyclohexene diepoxide (VCD)
We found that VCD exposure significantly increased the B-cell lymphoma 2 (Bcl-2) mRNA level in primordial follicles and did so in a dose-dependent manner
Summary
An ovary contains a finite pool of oocyte-containing follicles at different developmental stages, and this pool of dormant primordial follicles provides developing follicles and oocytes, known as the functional ovarian reserve (FOR) over the entire female reproductive lifespan as controlled by numerous regulatory signals (Adhikari and Liu, 2009). Women with diminished ovarian reserve (DOR) may experience menopausal symptoms including failure of follicle maturation and a significant decrease in ovarian gonad steroids such as estrogen, leading to a multitude of complications, e.g., cardiovascular diseases, osteoporosis, and cognitive impairment (Buckler, 2005). A growing list of natural and anthropogenic xenobiotics has been shown to perturb ovarian metabolism, menstrual cycles, and follicular development (Bhattacharya and Keating, 2012). These ovotoxicants have been shown to deregulate endocrine signaling, redox homeostasis, and epigenetic modifications and to impair ovarian functions and trigger broad or targeted follicular atresia, and induce DOR (Vabre et al, 2017)
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