Abstract
Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor–ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling–based drugs and their potential to function as endocrine disruptors.
Highlights
Whereas male mice exhibit decreased fertility [7]
We found 18 bisphenol derivatives with similar or stronger ERβ binding than bisphenol A (BPA) (Table 1 and Fig. S1)
The second strongest ERβ binding was seen with compound No 2 (4,40-(1,3-dimethylbutylidene)bisphenol; IC50 of 16.1 nM), higher affinity was measured with ERα (IC50 of 5.75 nM). 4,40-(1,3-Dimethylbutylidene)bisphenol, 2,2bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) [3], and BPAF showed comparable binding ability to ERβ (IC50 of 18 nM)
Summary
Whereas male mice exhibit decreased fertility [7]. Disruption of ERα in female mice leads to hypoplastic uteri, and ERα-disrupted female mice do not respond to estradiol treatments. Reporter assays using HeLa cells were performed to evaluate ERβ transcriptional activity induced by BPA, BPC, BPAF, and 17 bisphenol derivatives (Fig. 2B). These findings contrast with ERα, where the majority of bisphenol derivatives with strong binding affinity showed strong agonistic activity [34].
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