Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor
Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor
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DOI：
10.1093/toxsci/kfg150
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发表时间：
2003-09-01
影响因子：
3.8
通讯作者：
Lee, K
中科院分区：
文献类型：
--
作者：
Lee, HJ;Chattopadhyay, S;Lee, K
利用酵母检测系统检测化学物质的雄激素和抗雄激素作用，我们确定双酚A（BPA）和壬基酚（NP）为抗雄激素。在这项研究中，我们报告的BPA和NP的抗雄激素作用的分子机制。在ARhLBD激活信号共整合子1（ASC 1）酵母双杂交系统中，其反映了雄激素受体（AR）与其共激活子之间的雄激素依赖性相互作用，ASC 1、BPA和NP充当与已知的强拮抗剂醋酸环丙孕酮相当的有效AR拮抗剂。配体竞争试验显示，在约5 nM NP和50 nM BPA时，[H-3] 5 α-二羟基睾酮（DHT）与AR的结合分别被抑制最大30%和40%。此外，在睾酮存在下，绿色荧光蛋白（GFP）-AR融合蛋白的核转位受到BPA和NP的影响，这导致GFP-AR在细胞核和细胞质区室之间相当分散的分布。此外，在瞬时转染试验中，BPA和NP抑制雄激素诱导的AR转录活性。两者合计，结果表明，BPA和NP影响AR的激活和功能的多个步骤，从而抑制天然雄激素与AR的结合，AR核定位，AR与其辅助调节因子的相互作用，以及随后的反式激活。这些数据可以帮助我们更好地了解这些环境化合物引起的生物学变化。
By using a yeast detection system for androgenic and antiandrogenic effects of chemicals, we identified bisphenol A (BPA) and nonylphenol (NP) as antiandrogens. In this study, we report molecular mechanisms for the antiandrogenic action of BPA and NP. In the ARhLBD-activating signal cointegrator 1 (ASC1) yeast two-hybrid system, which reflects the androgen-dependent interaction between androgen receptor (AR) and its coactivator, ASC1, BPA and NP acted as potent AR antagonists comparable to a known strong antagonist, cyproterone acetate. Ligand competition assays revealed that [H-3]5alpha-dihydroxytestosterone (DHT) binding to AR is inhibited a maximum of 30 and 40% at approximately 5 nM of NP and 50 nM of BPA, respectively. In addition, the nuclear translocation of green fluorescent protein (GFP)-AR fusion protein in the presence of testosterone was affected by the addition of BPA and NP, which cause rather dispersed distribution of GFP-AR between the nuclear and the cytoplasmic compartments. Furthermore, in transient transfection assays, BPA and NP inhibited androgen-induced AR transcriptional activity. Taken together, the results suggest that BPA and NP affect multiple steps of the activation and function of AR, thereby inhibiting the binding of native androgens to AR, AR nuclear localization, AR interaction with its coregulator, and its subsequent transactivation. These data may help us better understand the biological alterations induced by these environmental compounds.