Hormone-Like Effects of 4-Vinylcyclohexene Diepoxide on Follicular Development

Lian Bao Cao; Hong Bin Liu; Gang Lu; Yue Lv; Chi Kwan Leung; Yan Zhi Du; Wu Ming Wang; Zhi Qiang Xiong; Xian Wei Su; Hong Jian Li; Zi-Jiang Chen; Jin Long Ma; Wai Yee Chan

doi:10.3389/fcell.2020.00587

Hormone-Like Effects of 4-Vinylcyclohexene Diepoxide on Follicular Development

Front Cell Dev Biol. 2020 Jul 31:8:587. doi: 10.3389/fcell.2020.00587. eCollection 2020.

Authors

Lian Bao Cao^{1

2

3}, Hong Bin Liu^{1

2

3}, Gang Lu^{2

3}, Yue Lv^{1

2

3}, Chi Kwan Leung^{1

2

3

4}, Yan Zhi Du^{3

5}, Wu Ming Wang^{2

3}, Zhi Qiang Xiong^{1

3

4}, Xian Wei Su^{1

2

3

4}, Hong Jian Li^{1

2

3

4}, Zi-Jiang Chen^{1

2

3

5}, Jin Long Ma^{1

2

3

4}, Wai Yee Chan^{2

3}

Affiliations

¹ Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
² CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
³ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.
⁴ SDIVF R&D Centre, Hong Kong Science and Technology Parks, Sha Tin, China.
⁵ Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: 4-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.

Results: We 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 (VCD^low) actually protects the primordial/primary follicle pool and improves the functional ovarian reserve (FOR) by disrupting follicular atresia. VCD^low 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.

Conclusion: Our study illustrates a previously unappreciated, hormone-like action for the occupational "ovotoxin" molecule VCD and strongly suggests that VCD^low should be explored for its potential utility for treating human ovarian follicular development disorders, including subfertility in perimenopausal women.

Keywords: PI3K-Akt pathway; VCD; folliculogenesis; ovotoxicity; ovulation induction.