Chronic exposure to bisphenol a impairs progesterone receptor-mediated signaling in the uterus during early pregnancy.
Chronic exposure to bisphenol a impairs progesterone receptor-mediated signaling in the uterus during early pregnancy.
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DOI：
10.14800/rci.1369
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Bagchi, Indrani C
中科院分区：
文献类型：
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作者：
Li, Quanxi;Davila, Juanmahel;Bagchi, Indrani C
环境和职业接触内分泌干扰化学品（EDCs）是对女性生殖健康的主要威胁。双酚A （BPA）是一种常见于聚碳酸酯塑料和环氧树脂中的环境有毒物质，因其具有雌激素活性和人体长期暴露的高风险而受到广泛关注。尽管BPA与女性不孕和反复流产有关，但其对妊娠早期子宫功能的影响尚不清楚。在最近发表于《内分泌学》（Endocrinology）的一篇文章中，我们证明了长期暴露于环境相关剂量的BPA会破坏黄体酮受体调节的子宫功能，从而影响子宫对胚胎着床和蜕膜形态发生的接受性，这是早期妊娠建立和维持的两个关键事件。我们特别报道了慢性双酚a暴露后子宫基质细胞中孕激素受体（PGR）及其下游效应物HAND2表达的显著损伤。在早期的研究中，我们发现HAND2通过抑制成纤维细胞生长因子（FGF）表达和MAP激酶信号通路来控制胚胎着床，从而抑制上皮细胞增殖。有趣的是，我们观察到BPA暴露后子宫间质中PGR和HAND2表达的下调与FGFR和MAPK信号激活增强、异常增殖和子宫上皮缺乏接受性有关。此外，子宫内膜基质细胞向蜕膜细胞的增殖和分化是维持早期妊娠的关键事件，BPA的反应严重损害了子宫内膜基质细胞的增殖和分化。本研究重点将概述我们的研究结果，并讨论慢性双酚a损害PGR-HAND2通路并对着床和妊娠产生不利影响的潜在机制。
Environmental and occupational exposure to endocrine disrupting chemicals (EDCs) is a major threat to female reproductive health. Bisphenol A (BPA), an environmental toxicant that is commonly found in polycarbonate plastics and epoxy resins, has received much attention due to its estrogenic activity and high risk of chronic exposure in human. Whereas BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In a recent publication in Endocrinology, we demonstrated that prolonged exposure to an environmental relevant dose of BPA disrupts progesterone receptor-regulated uterine functions, thus affecting uterine receptivity for embryo implantation and decidua morphogenesis, two critical events for establishment and maintenance of early pregnancy. In particular we reported a marked impairment of progesterone receptor (PGR) expression and its downstream effector HAND2 in the uterine stromal cells in response to chronic BPA exposure. In an earlier study we have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor (FGF) expression and the MAP kinase signaling pathway, thus inhibiting epithelial proliferation. Interestingly we observed that downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with an enhanced activation of FGFR and MAPK signaling, aberrant proliferation, and lack of uterine receptivity in the epithelium. In addition, the proliferation and differentiation of endometrial stromal cells to decidual cells, an event critical for the maintenance of early pregnancy, was severely compromised in response to BPA. This research highlight will provide an overview of our findings and discuss the potential mechanisms by which chronic BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy.