Bisphenol AF and Bisphenol B Exert Higher Estrogenic Effects than Bisphenol A via G Protein-Coupled Estrogen Receptor Pathway,Environmental Science & Technology

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Bisphenol AF and Bisphenol B Exert Higher Estrogenic Effects than Bisphenol A via G Protein-Coupled Estrogen Receptor Pathway
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2017-09-14 00:00:00 , DOI: 10.1021/acs.est.7b03336
Lin-Ying Cao _{1,

2} , Xiao-Min Ren ₁ , Chuan-Hai Li _{1,

2} , Jing Zhang ₁ , Wei-Ping Qin _{1,

2} , Yu Yang ₁ , Bin Wan ₁ , Liang-Hong Guo _{1,

2}

Affiliation

Numerous studies have indicated estrogenic disruption effects of bisphenol A (BPA) analogues. Previous mechanistic studies were mainly focused on their genomic activities on nuclear estrogen receptor pathway. However, their nongenomic effects through G protein-coupled estrogen receptor (GPER) pathway remain poorly understood. Here, using a SKBR3 cell-based fluorescence competitive binding assay, we found six BPA analogues bound to GPER directly, with bisphenol AF (BPAF) and bisphenol B (BPB) displaying much higher (∼9-fold) binding affinity than BPA. Molecular docking also demonstrated the binding of these BPA analogues to GPER. By measuring calcium mobilization and cAMP production in SKBR3 cells, we found the binding of these BPA analogues to GPER lead to the activation of subsequent signaling pathways. Consistent with the binding results, BPAF and BPB presented higher agonistic activity than BPA with the lowest effective concentration (LOEC) of 10 nM. Moreover, based on the results of Boyden chamber and wound-healing assays, BPAF and BPB displayed higher activity in promoting GPER mediated SKBR3 cell migration than BPA with the LOEC of 100 nM. Overall, we found two BPA analogues BPAF and BPB could exert higher estrogenic effects than BPA via GPER pathway at nanomolar concentrations.

中文翻译：

双酚AF和双酚B通过G蛋白偶联的雌激素受体途径比双酚A发挥更高的雌激素作用

大量研究表明双酚A（BPA）类似物的雌激素破坏作用。先前的机理研究主要集中在它们在核雌激素受体途径上的基因组活性。但是，它们通过G蛋白偶联雌激素受体（GPER）途径的非基因组作用仍然知之甚少。在这里，我们使用基于SKBR3细胞的荧光竞争结合测定法，发现了六个直接与GPER结合的BPA类似物，双酚AF（BPAF）和双酚B（BPB）的结合亲和力比BPA高得多（约9倍）。分子对接也证明了这些BPA类似物与GPER的结合。通过测量SKBR3细胞中的钙动员和cAMP产生，我们发现这些BPA类似物与GPER的结合导致后续信号通路的激活。与绑定结果一致，BPAF和BPB的激动活性高于BPA，最低有效浓度（LOEC）为10 nM。此外，根据博伊登室和伤口愈合试验的结果，BPAF和BPB在LOEP为100 nM的情况下，在促进GPER介导的SKBR3细胞迁移方面显示出比BPA更高的活性。总体而言，我们发现在纳摩尔浓度下，两种BPA类似物BPAF和BPB可以通过GPER途径发挥比BPA更高的雌激素作用。

更新日期：2017-09-14

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