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

Bisphenol A (BPA) and bisphenol S (BPS) are agonists of hER alpha 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)alpha agonist and antagonist activities with the validated OECD assay with the hER alpha-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 hER alpha, 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 hER alpha agonists were even more potent than BPA, as bisphenol B and C, with IC50 values of 0.31 mu M and 0.48 mu M, respectively. Among these selected bisphenols, 4-4'-methylenebis (oxyethylenethio) diphenol was the most potent hER alpha antagonist, with an IC50 of 0.39 mu M. 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.