Exploring the Antagonistic Effects of Bisphenols with Nonmonotonic Dose-Response Curves on the Estrogen Receptor

The nonmonotonic dose-response curve (NMDRC) is a prevalent characteristic of endocrine-disrupting chemicals (EDCs) in activating nuclear receptors (NRs), implicating intricate regulatory mechanisms. In this study, the agonistic and antagonistic activities of 11 bisphenols on the estrogen receptor (ER) were screened using MVLN cells. Three distinct dose-response patterns were observed, namely, S-shaped, inverted S-shaped, and bell-shaped profiles, corresponding to the agonistic, antagonistic, and nonmonotonic effects on ERs, respectively. To further explore NMDRC, bisphenol B (BPB) and bisphenol AF (BPAF), as representative compounds, were specifically investigated for their antagonistic effects on ER under high exposure concentrations (10-50 μmol/L). Notably, the successive decline in cell viability suggested a subhealthy cell state upon high-dose chemical treatments, compromising cell response in ER transactivation. Unlike the specific effect induced by an ERα antagonist (4-hydroxytamoxifen, 4OHT), the nonspecific inhibitory effects of BPB and BPAF on ER transactivation were further confirmed with their identical antagonistic curves, with or without E2 cotreatment, due to hydrophobicity-related cellular baseline toxicity. Accordingly, the inhibitory effects on NR transactivation might not necessarily be considered as a specific antagonistic activity. Thus, a more cautious inspection is highly encouraged in screening NR antagonism-centered endocrine-disrupting effects of emerging chemicals by carefully reviewing the specificity of signal reduction or inhibition.