Department of Health Toxicology, School of Public Health, 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; School of Basic Medicine, Chongqing Medical University, Chongqing 400016, PR China.
Sci Total Environ. 2024 May 15;925:171790. doi: 10.1016/j.scitotenv.2024.171790. Epub 2024 Mar 18.
Fenvalerate (FEN), a type II pyrethroid pesticide, finds extensive application in agriculture, graziery and public spaces for pest control, resulting in severe environmental pollution. As an environmental endocrine disruptor with estrogen-like activity, exposure to FEN exhibited adverse effects on ovarian functions. Additionally, the presence of the metabolite of FEN in women's urine shows a positive association with the risk of primary ovarian insufficiency (POI). In mammals, the primordial follicle pool established during the early life serves as a reservoir for storing all available oocytes throughout the female reproductive life. The initial size of the primordial follicle pool and the rate of its depletion affect the occurrence of POI. Nevertheless, there is very limited research about the impact of FEN exposure on primordial folliculogenesis. In this study, pregnant mice were orally administrated with 0.2, 2.0 and 20.0 mg/kg FEN from 16.5 to 18.5 days post-coitus (dpc). Ovaries exposed to FEN exhibited the presence of large germ-cell cysts that persist on 1 days post-parturition (1 dpp), followed by a significant reduction in the total number of oocytes in pups on 5 dpp. Moreover, the levels of m6A-RNA and its associated proteins METTL3 and YTHDF2 were significantly increased in the ovaries exposed to FEN. The increased YTHDF2 promoted the assembly of the cytoplasmic processing bodies (P-body) in the oocytes, accompanied with altered expression of transcripts. Additionally, when YTHDF2 was knocked-down in fetal ovary cultures, the primordial folliculogenesis disrupted by FEN exposure was effectively restored. Further, the female offspring exposed to FEN displayed ovarian dysfunctions reminiscent of POI in early adulthood, characterized by decreases in ovarian coefficient and female hormone levels. Therefore, the present study revealed that exposure to FEN during late pregnancy disrupted primordial folliculogenesis by YTHDF2-mediated P-body assembly, causing enduring adverse effects on female fertility.
氰戊菊酯（FEN）是一种 II 型拟除虫菊酯农药，广泛应用于农业、畜牧业和公共空间的害虫防治，导致严重的环境污染。作为一种具有雌激素样活性的环境内分泌干扰物，FEN 的暴露对卵巢功能产生了不良影响。此外，女性尿液中 FEN 代谢物的存在与原发性卵巢功能不全（POI）的风险呈正相关。在哺乳动物中，原始卵泡库在生命早期建立，作为整个雌性生殖生命中所有可用卵母细胞的储存库。原始卵泡库的初始大小及其耗竭率影响 POI 的发生。然而，关于 FEN 暴露对原始卵泡发生的影响的研究非常有限。在这项研究中，从妊娠 16.5 天到 18.5 天，怀孕的老鼠通过口服接受 0.2、2.0 和 20.0mg/kg 的 FEN。暴露于 FEN 的卵巢中存在大的生殖细胞囊肿，这些囊肿在产后 1 天（1 dpp）持续存在，随后在 5 dpp 时幼崽中的卵母细胞总数显著减少。此外，暴露于 FEN 的卵巢中的 m6A-RNA 及其相关蛋白 METTL3 和 YTHDF2 的水平显著增加。增加的 YTHDF2 促进了卵母细胞中细胞质处理体（P 体）的组装，伴随着转录物的改变表达。此外，当胎儿卵巢培养物中敲低 YTHDF2 时，FEN 暴露破坏的原始卵泡发生得到有效恢复。此外，暴露于 FEN 的雌性后代在成年早期表现出类似于 POI 的卵巢功能障碍，表现为卵巢系数和女性激素水平降低。因此，本研究表明，妊娠晚期暴露于 FEN 通过 YTHDF2 介导的 P 体组装破坏原始卵泡发生，对女性生育能力产生持久的不良影响。
