New bisphenol A and bisphenol S analogs: Evaluation of their hERα agonistic and antagonistic activities using the OECD 455 in-vitro assay and molecular modeling.

Bisphenol A (BPA) and bisphenol S (BPS) are agonists of hERα receptors and due to BPA regulations in many countries, several substitutes that are close analogs to BPA and BPS were developed. In the presented study, we have determined human estrogen receptor (hER)α agonist and antagonist activities with the validated OECD assay with the hERα-Hela9903 cell line for five different chemical classes of BPA and BPS analogs. This study also defined clear structure-activity relationships for agonist and antagonist activities of the 12 bisphenols on hERα, which are supported by molecular docking studies. These data show that classical analogs of BPA (e.g., bisphenols B, C, AP, E) have comparable or superior estrogenic agonist potencies compared to BPA and BPS. The most potent of these hERα agonists were even more potent than BPA, as bisphenol B and C, with IC50 values of 0.31 µM and 0.48 µM, respectively. Among these selected bisphenols, 4-4'-methylenebis (oxyethylenethio)diphenol was the most potent hERα antagonist, with an IC50 of 0.39 µM. The estrogenic agonist and antagonist potencies of these different chemical classes of BPA and BPS analogs are mutually comparable and can be used as a basis for further structure-activity relationships studies and human risk assessment.