Impacts of Bisphenol A on Female Reproductive Health and Its Transgenerational Effects
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摘要: 双酚A（isphenol A，BPA）是一种类雌激素化合物，广泛存在于生活环境中，也是对人体危害较为广泛的一种环境内分泌干扰物。近年来，BPA对女性生殖健康的负面影响日益受到关注。现有证据表明，BPA通过干扰激素信号通路、诱导氧化应激与炎症反应、破坏表观遗传调控等多种机制，损害子宫内膜容受性、卵巢储备功能及卵母细胞质量，并且具有跨代遗传效应。将从BPA的来源与代谢特点、对子宫内膜容受性的影响、对卵巢与卵母细胞的损害及其跨代效应等方面进行综述。Abstract: Bisphenol A （BPA） is an estrogen-like compound widely present in daily life and is one of the compounds extensively studied for its harmful effects on human health. In recent years, increasing attention has been paid to the negative impact of BPA on female reproductive health. Accumulating evidence indicates that BPA impairs endometrial receptivity, ovarian function, and oocyte quality through multiple mechanisms, such as interfering with hormone signaling, inducing oxidative stress and inflammation, and disrupting epigenetic regulation. Furthermore, BPA has been shown to exert transgenerational effects. This article summarizes the sources and metabolism of BPA, its effects on endometrial receptivity, its damage to the ovaries and oocytes, and its transgenerational effects.
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Key words:
- Bisphenol A /
- Endometrium /
- Decidualization /
- Ovarian reserve /
- Oocyte /
- Transgenerational effect
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图 1 BPA通过内膜基质细胞的损伤和阻碍蜕膜化的双重作用损害子宫内膜功能
Figure 1. Dual effects of BPA on endometrial function through impairment of endometrial stromal cells and inhibition of decidualization
表 1 细胞和动物实验的研究
Table 1. Design of cellular and animal experiments
实验对象 BPA浓度/剂量 主要发现（结果） 参考文献 人原代子宫内膜基质细胞（ESCs） 10、100、 1000 pmol（0.01～1nM）BPA诱导ROS生成，下调抗氧化酶（SOD、HO-1、CAT），激活MAPK/NF-κB通路，上调促炎因子（TNF-α、IL-6、IL-1β），效应由ERα介导 Cho YJ et al[37] St-T1b细胞 10 µM（实验）；范围1 nM～20 µM BPA诱导凋亡（激活caspase-3/7）。 Ferreira R et al[38] 人原代及永生化子宫内膜
基质细胞（ESCs/ HESCs）10 pM～ 10 µM BPA通过ER抑制蜕膜化，下调HOXA10/PRL/IGFBP-1；下调MLL1（H3K4me3）、上调EZH2（H3K27me3），改变关键基因启动子区组蛋白修饰 Xiong Y et al[11] Ishikawa和Jeg-3球体 1～100 µM BPA（10～100 µM）抑制球体附着；下调ERα/ERβ/GPR30，上调PR Fan H et al[10] 成年雌性C57BL/6小鼠（整体） 60 [µg/（kg·d）]（经口灌胃） 增加子宫重量和腺体/基质比例，诱导腺上皮异常增殖；通过Hand2启动子CpG高甲基化下调HAND2；激活MAPK通路。 Neff AM et al[41] CD-1雌性小鼠（整体，延迟着床模型） 60、600 [µg/（kg·d）]（经口灌胃） BPA 60 [µg/（kg·d）]损害着床和蜕膜化；下调子宫基质PGR和HAND2，激活FGF/MAPK通路，上皮持续增殖，基质细胞蜕膜化受阻 Li Q et al[42] 人原代颗粒细胞 0.001、0.1、100 µM 100 µM BPA降低细胞活力、抑制E2和P4合成；0.001和0.1 µM改变类固醇生成和凋亡相关基因表达 Celar Sturm D et al[44] 人颗粒细胞系（KGN） 0.1- 100 µM 100 µM BPA抑制增殖、诱导自噬（LC3-II↑、p62↓），通过miR-204靶向BDNF抑制NTRK2/PI3K/Akt/mTOR通路；miR-204抑制剂可逆转 Li C et al[45] 小鼠+KGN细胞 小鼠：1- 100 [µg/（kg·d）]; 细胞：1- 100 nM 小鼠：E2、P4、AMH下降，卵泡囊性扩张；细胞：BPA通过AMPK/mTOR/ULK1通路诱导自噬和凋亡 Lin M et al[46] 成年雌性Sprague-Dawley大鼠 0.001、0.1 [µg/（kg·d）] BPA降低E2和T，增加LH；下调颗粒细胞P450arom（芳香化酶）和膜-间质细胞StAR；加剧卵泡闭锁和黄体退化（caspase-3凋亡） Lee SG et al[55] 小鼠窦前卵泡 10 µg/mL（≈43.8 µM） 促进晚期颗粒细胞增殖（PCNA↑、E2/P4↑），但损害卵丘扩展和缝隙连接（Cx37↓）；促进GVBD但导致MII成熟率下降（cyclin B1异常升高） Li Y et al[58] 人原代颗粒细胞（GC/M-AO细胞） 10-⁷M（=0.1µM） BPA通过ER和MAPK通路下调Cx43表达，抑制颗粒细胞间缝隙连接通讯（GJIC） Lin TC et al[56] 绵羊胎儿卵巢组织块（器官培养） 3×10-⁷M、3×10-⁵ M 下调减数分裂标志基因（STRA8、DMC1、SYCP1、SPO11）；30 µM改变677个探针表达，富集于细胞周期、减数分裂、纺锤体组装通路 Loup B et al[61] 小鼠卵母细胞（IVM） 50、100、200 µM 100 µM BPA降低极体排出率；线粒体分布异常、膜电位下降；内质网应激（GRP78↑） Pan MH et al[62] 雌性ICR小鼠（整体） 100 [µg/（kg·d）] BPA降低极体排出率，破坏纺锤体/染色体，增加非整倍体；降低受精率（Juno丢失→膜融合受阻） Zhang M et al[63] 雌性C57BL/6J小鼠（整体） 50[µg/（kg·d）]（经口灌胃） BPA不影响排卵，但显著降低IVF和体内受精率；去除卵丘细胞后效应仍存在，靶点为卵母细胞本身；不影响早期胚胎发育 Moore-Ambriz TR et al[64] 小鼠卵母细胞（IVM） 20、50、100 µg/mL（50 µg/mL≈ 219 µM） 50 µg/mL BPA抑制极体排出、降低IVF率和囊胚率；ROS↑、GSH↓ Li Q et al[65] 
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表 2 人群流行病学研究
Table 2. Population-based epidemiological study
实验对象 BPA浓度/剂量 主要发现（结果） 参考文献 256名IVF女性（EARTH队列，多种不孕病因） 尿BPA SG校正几何均数1.87 µg/L，约8.19 nM BPA与获卵数、受精率、优质胚胎率、着床率、临床妊娠率、活产率均无显著关联（仅年龄交互作用影响内膜厚度） Mínguez-Alarcón L et al[43] 106名IVF女性 尿BPA中位0.743 µg/L，约 3.25 nM 高BPA组（>0.743µg/L）取卵率、成熟率、着床率降低 Lin M et al[46] 511名不孕女性（波兰，生育诊所） 尿BPA几何均数1.38 ng/mL（SG校正1.60 ng/mL，约 7.01 nM） BPA与AMH（P= 0.02）和AFC（P= 0.03）显著负相关；与FSH、E2无关联 Czubacka E et al[51] 154–209名IVF女性（EARTH队列早期，美国） 尿BPA SG校正几何均数1.5- 1.7 µg/L，约6.57 – 7.44 nM BPA与AFC显著负相关（趋势P< 0.001），Q3和Q4分别降低22%和17%；与FSH、卵巢体积无关联 Souter I et al[52] 111名辅助生殖女性（中国沈阳） BPA：4.22 µg/g Cr；（Cr校正几何均数） BPA与AFC负相关 Zhang N et al[53] 307名育龄女性（韩国，普通志愿者） 尿BPA：DOR组1.89 vs 非DOR组1.58 µg/g Cr（p=0.009） BPA与DOR（AMH< 25百分位）显著相关；高BPA暴露组不孕风险OR=4.248（调整后）； Park SY et al[54] 90名IVF女性（伊朗） 卵泡液BPA≥150 ng/mL，血清BPA≥150 ng/mL，约657 nM 高卵泡液BPA与GV和退化卵母细胞增多相关；血清BPA≤50 ng/mL组MII卵数显著更多；血清BPA≥150 ng/mL组GV卵数显著增多 Poormoosavi SM et al[66] 351名输卵管因素不孕IVF女性（中国） 尿BPA Cr校正中位数0.720 µg/g Cr BPA高浓度组获卵数减少（P= 0.02）；着床率和临床妊娠率显著降低；冻融周期中无关联，提示BPA主要靶点为子宫内膜容受性 Shen J et al[68]
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