Reproductive Science Group, School of Environmental & Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia.
Toxicol Sci. 2012 Jul;128(1):258-71. doi: 10.1093/toxsci/kfs137. Epub 2012 Apr 12.
3-Methylcholanthrene (3MC) is a potent ovotoxicant capable of causing premature ovarian failure through primordial follicle depletion. Despite 3MCs ovotoxicity having been established for 30 years, relatively little information exists on the mechanisms. In this study, we examined the effects of 3MC exposure on the immature ovarian follicle population. Microarray analysis revealed a complex mechanism of 3MC-induced ovotoxicity involving a number of cellular processes associated with xenobiotic metabolism, ovarian cancer, cell cycle progression, and cell death. 3MC exposure was also found to induce developing follicle atresia and aberrant primordial follicle activation via the stimulation of PI3K/Akt and mammalian target of rapamycin (mTOR) signaling pathways. Inhibition of PI3K/Akt signaling resulted in the severe depletion of the primordial follicle pool, with further analysis identifying increased Akt1-stimulated Bad phosphoinhibition in 3MC-treated primordial follicles. Our results suggest that the primordial follicle pool enters a "prosurvival" state upon 3MC exposure and that its depletion is due to a vicious cycle of primordial follicle activation in an attempt to replace developing follicles undergoing follicular atresia.
3-甲基胆蒽（3MC）是一种强效的卵毒性物质，能够通过原始卵泡耗竭导致卵巢早衰。尽管 3MC 的卵毒性已经确立了 30 年，但关于其机制的信息相对较少。在这项研究中，我们研究了 3MC 暴露对未成熟卵巢卵泡群体的影响。微阵列分析揭示了 3MC 诱导的卵毒性的复杂机制，涉及许多与外源性代谢物、卵巢癌、细胞周期进展和细胞死亡相关的细胞过程。研究还发现，3MC 暴露通过刺激 PI3K/Akt 和哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，诱导正在发育的卵泡闭锁和异常原始卵泡激活。抑制 PI3K/Akt 信号通路导致原始卵泡库严重耗竭，进一步分析表明，在 3MC 处理的原始卵泡中，Akt1 刺激的 Bad 磷酸化抑制增加。我们的研究结果表明，原始卵泡库在 3MC 暴露后进入“存活促进”状态，其耗竭是由于原始卵泡激活的恶性循环，试图替代正在经历卵泡闭锁的发育卵泡。
