College of Basic Medicine, Chongqing Medical University, Chongqing 400016, PR China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing 400016, PR China.
Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, PR China.
Ecotoxicol Environ Saf. 2022 May 1;236:113480. doi: 10.1016/j.ecoenv.2022.113480. Epub 2022 Apr 6.
The primordial follicle pool established in early life determines the ovarian reserve in the female reproductive lifespan. Premature exhaustion of primordial follicles contributes to primary ovarian insufficiency (POI), that is dependent by the initial size of the primordial follicle pool and by the rate of its activation and depletion. AAI, a powerful nephrotoxin with carcinogenic potential, is present in the Aristolochiaceae species, which can release AAI into soil as a persistent pollutant. In order to assess the potential risk of Aristolochic Acid I (AAI) exposure on mammalian oogenesis, we uncovered its adverse effect on primordial folliculogenesis in the neonatal mouse ovary and its effect on female fertility in adulthood. Pregnant mice were orally administrated with doses of AAI without hepatic or renal toxicity during late-gestation. Ovaries from offspring of administered female displayed gross aberrations during primordial folliculogenesis. Also, unenclosed oocytes in germ-cell cysts showed increased DNA damage. Furthermore, several key factors, including NANOS3, SOX9, KLF4, that govern early gonad's differentiation were abnormally expressed in the exposed ovary, while the follicle formation was partially restored by knockdown of Nanos3 or sox9. In adulthood, these aberrations evolved into a significant reduction in offspring number and impaired ovarian reserve. Together, our results show that AAI influences primordial folliculogenesis and, importantly, affected female fertility. This study shows that administration of drugs herbs or consumption of vegetables that contain AAs during pregnancy may adversely influence the fertility of offspring.
原始卵泡池在生命早期建立，决定了女性生殖寿命中的卵巢储备。原始卵泡的过早耗竭导致原发性卵巢功能不全（POI），这取决于原始卵泡池的初始大小及其激活和耗竭的速度。马兜铃酸（AA）是一种具有肾毒性和潜在致癌性的物质，存在于马兜铃科植物中，这些植物会将 AA 作为持久性污染物释放到土壤中。为了评估 AA 暴露对哺乳动物卵母细胞发生的潜在风险，我们揭示了其对新生小鼠卵巢原始卵泡发生的不良影响及其对成年雌性生育力的影响。在妊娠晚期，给怀孕的小鼠口服 AA 剂量，不会产生肝毒性或肾毒性。接受 AA 处理的雌性后代的卵巢在原始卵泡发生过程中出现明显异常。此外，在生殖细胞囊中未被包裹的卵母细胞显示出 DNA 损伤增加。此外，包括 NANOS3、SOX9、KLF4 在内的几个关键因子，它们控制着早期性腺的分化，在暴露的卵巢中异常表达，而通过敲低 Nanos3 或 Sox9，卵泡形成部分得到恢复。在成年期，这些异常发展为后代数量显著减少和卵巢储备受损。总之，我们的结果表明，AA 影响原始卵泡发生，重要的是，影响雌性生育力。这项研究表明，在怀孕期间服用含有 AA 的药物、草药或食用含有 AA 的蔬菜可能会对后代的生育能力产生不利影响。
