Molecular mechanism of Bisphenol A on androgen receptor antagonism
Molecular mechanism of Bisphenol A on androgen receptor antagonism
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双酚A拮抗雄激素受体的分子机制
DOI：
10.1016/j.tiv.2019.104621
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发表时间：
2019-12-01
影响因子：
3.2
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Huang, Xin;Cang, Xiaohui;Liu, Jing
双酚A（BPA）是产量最高的化学品之一，也是一种典型的内分泌干扰化学品（EDC），具有抗雄激素活性。然而，BPA如何拮抗雄激素的作用仍不明确。本研究通过计算机模拟和体外实验，探讨BPA拮抗雄激素受体（AR）的分子机制。在报告基因测定中，BPA在10（-9）M-10（-5）M浓度下对5 α-二氢睾酮（DHT）诱导的AR转录活性产生显著的拮抗作用。分子对接和分子动力学模拟的结果表明BPA与AR的配体结合域结合的有效性。BPA处理阻止了由DHT与AR结合引起的受体降解的抑制。BPA暴露也废除了DHT依赖的AR从其共伴侣，90 kDa的热休克蛋白（Hsp 90）的解离，并导致DHT诱导的AR核转位的阻断。这是第一次报道BPA抑制DHT诱导的AR的稳定和DHT诱导的AR-Hsp 90复合物的解离。本研究为进一步了解BPA拮抗AR的确切机制提供了新的证据。
Bisphenol A (BPA), one of the highest production volume chemicals, is a typical endocrine-disrupting chemical (EDC) that exhibits antiandrogenic activity. However, how BPA antagonizes androgen effects remains ambiguous. In this study, the in silico and in vitro assays were carried out to explore the molecular mechanism(s) of BPA on androgen receptor (AR) antagonism. In reporter gene assay, BPA caused a significant antagonistic effect on 5 alpha-dihydrotestosterone (DHT)-induced AR transcriptional activity at concentrations of 10(-9) M-10(-5) M. The results of molecular docking and molecular dynamics simulations indicated the availability of BPA binding to the ligand binding domain of AR. BPA treatment prevented the inhibition of receptor degradation caused by DHT binding to AR. BPA exposure also abolished DHT-dependent dissociation of AR from its co-chaperone, 90-kDa heat shock protein (Hsp90), and resulted in the blockage of DHT-induced AR nuclear translocation. This is the first report to show that BPA inhibited the DHT-induced stabilization of AR and the DHT-induced dissociation of AR-Hsp90 complex. This study provided new evidence for further understanding the precise mechanisms of antagonism of BPA on AR.