Prenatal exposure to propylparaben at human-relevant doses accelerates ovarian aging in adult mice
Prenatal exposure to propylparaben at human-relevant doses accelerates ovarian aging in adult mice
复制标题
产前接触人类相关剂量的对羟基苯甲酸丙酯会加速成年小鼠的卵巢衰老
DOI：
10.1016/j.envpol.2021.117254
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发表时间：
2021-05-03
影响因子：
8.9
通讯作者：
Wang, Shixuan
中科院分区：
文献类型：
--
作者：
Li, Milu;Zhou, Su;Wang, Shixuan
胚胎暴露于环境化学物质可能会导致成年后特定的慢性疾病。对羟基苯甲酸酯是一种广泛用于药品和化妆品的环境内分泌干扰物，已被证明会导致女性生殖功能下降。然而，怀孕期间接触对羟基苯甲酸酯是否也会对成年雌性后代的卵巢功能产生负面影响仍不清楚。本研究旨在探讨孕期暴露于帕金森丙酯(PrP)对46周龄(相当于40岁)成年小鼠卵巢功能的影响。妊娠ICR小鼠在胚胎性别判定期间，从胚胎e7.5天到胚胎13.5天，分别给予人相应剂量的PrP(即0、7.5、90和450 mg/kg/天)。结果表明，暴露于PrP的46周小鼠卵巢老化加速，动情周期的规律性改变，血清雌二醇(E_2)和孕酮(P_4)水平降低，原始卵泡池缩小，闭锁卵泡数增加。研究发现，产前暴露于人类相关剂量的PrP会加剧卵巢氧化应激、炎症和纤维化，从而通过激活线粒体凋亡途径促进卵泡闭锁。作为补偿，PrP暴露的小鼠通过激活PI3K/AKT/mTOR信号通路也加速了原始卵泡的耗竭。此外，PrP诱导Cyp11a1启动子区域CpG位点的超甲基化(增加17.16e64.28%)部分导致类固醇合成中断，印迹基因H19和Peg3甲基化水平的改变也可能与观察到的表型有关。这些显着的发现强调了卵巢老化的胚胎起源，并建议在怀孕期间减少PrP的使用。0 2021爱思唯尔有限公司。保留所有权利。
Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination perioddfrom embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16e64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated. 0 2021 Elsevier Ltd. All rights reserved.