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.

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.

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.

4-乙烯基环己烯二环氧化物 (VCD) 长期以来一直被认为是一种危险的职业化学物质，可促进卵巢功能衰竭。然而，VCD 也被用作化学诱导卵巢功能不全（POI）动物模型的研究化合物，在相关工作中，我们意外地发现 VCD 明显表现出剂量和持续时间依赖性的对立激素样作用对维持原始卵泡池、卵泡发育和排卵诱导。

我们对培养的小鼠卵巢进行了实验，并使用出生后第 2 天 (PD) 2 和 PD12 小鼠进行了移植实验，发现低剂量、短期暴露于 VCD (VCD ^low ) 实际上可以保护原始/初级卵泡池并改善功能卵巢储备（FOR）通过破坏卵泡闭锁。VCD ^low抑制滤泡凋亡并调节 Pten-PI3K-Foxo3a 通路。短期 VCD 曝光体内(80 mg/kg, 5 天) 显着增加卵巢储备减少 (DOR) 的中年小鼠超排卵中期 II 卵母细胞、排卵前卵泡和黄体的数量。我们证明低剂量而非高剂量 VCD 可促进颗粒细胞 (GC) 中的芳香酶水平，从而提高雌二醇分泌水平。

我们的研究说明了职业性“卵毒素”分子 VCD 具有以前未被重视的激素样作用，并强烈建议应探索^低VCD治疗人类卵巢卵泡发育障碍的潜在效用，包括围绝经期妇女的生育能力低下。