BPA activates EGFR and ERK1 /2 through PPARγ to increase expression of steroidogenic acute regulatory protein in human cumulus granulosa cells
BPA activates EGFR and ERK1 /2 through PPARγ to increase expression of steroidogenic acute regulatory protein in human cumulus granulosa cells
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DOI：
10.1016/j.chemosphere.2019.04.174
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发表时间：
2019-08-01
期刊：
影响因子：
8.8
通讯作者：
Andric, Nebojsa
中科院分区：
文献类型：
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作者：
Pogrmic-Majkic, Kristina;Nenadov, Dragana Samardzija;Andric, Nebojsa
双酚A（SPA）对人黄素化颗粒细胞（GC）中类固醇的产生有负面影响。本研究旨在解决两个重要问题：（1）BPA是否在人类卵丘颗粒细胞（hCGC）中发挥相同的破坏作用;（2）揭示BPA对类固醇生成作用的分子机制。我们使用培养的hCGC，因为这些细胞发挥早期窦卵泡CC的特性。结果显示，100 μ M BPA可降低雌二醇水平和CYPI 9 AI mRNA，但48 h后可增加孕酮产生、类固醇生成急性调节蛋白（星星）和过氧化物酶体增殖物激活受体γ（PPAR γ）mRNA表达。BPA暴露时间较短（6 h），hCGC中的PPAR γ mRNA水平升高。添加ERK 1/2（U 0126）、EGFR（AG 1478）和PPARgamma（GW 9662）抑制剂可阻止BPA诱导的星星和PPARgamma mRNA表达。Western blot分析显示BPA诱导EGFR和ERK 1/2快速活化。BPA诱导的EGFR磷酸化通过加入PPAR γ抑制剂来阻止，而BPA诱导的ERK 1/2激活通过加入EGFR或PPAR γ抑制剂来阻止。这些数据表明BPA增加了hCGC中的孕酮并减少了雌二醇生物合成途径。孕酮生物合成途径的增强通过EGFR和ERK 1/2的PPAR γ依赖性活化介导，导致星星mRNA表达增加。(C)2019爱思唯尔有限公司版权所有。
Bisphenol A (SPA) negatively affects steroid production in human luteinized granulosa cells (GC). This study was designed to address two important questions: (1) whether BPA exerts the same disruptive effect in human cumulus granulosa cells (hCGC) and (2) to reveal the molecular mechanism underlying the BPA's action on steroidogenesis. We used cultured hCGC since these cells exert the properties of CC from early antral follicles. Results showed that BPA at 100 mu M decreased estradiol level and CYPI9AI mRNA, but increased progesterone production, steroidogenic acute regulatory protein (STAR) and peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA expression after 48 h. Shorter (6 h) exposure to BPA elevated PPAR gamma mRNA level in hCGC. Addition of ERK1/2 (U0126), EGFR (AG1478) and PPAR gamma (GW9662) inhibitors prevented the BPA-induced STAR and PPAR gamma mRNA expression. Western blot analysis showed that BPA induced a rapid EGFR and ERK1/2 activation. The BPA-induced EGFR phosphorylation was prevented by addition of the PPAR gamma inhibitor, whereas the BPA-induced ERK1 /2 activation was prevented by addition of the EGFR or PPAR gamma inhibitor. These data show that BPA increases the progesterone and decreases the estradiol biosynthetic pathway in hCGC. Augmentation of the progesterone biosynthetic pathway is mediated through the PPAR gamma-dependent activation of EGFR and ERK1/2, leading to increased expression of STAR mRNA. (C) 2019 Elsevier Ltd. All rights reserved.