Differential in Vitro Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand–ERα Complexes

Abstract

Background:Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood.Objectives:Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERα) complex.Methods:In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex.Results:We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERβ, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER–ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes.Conclusion:These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health. https://doi.org/10.1289/EHP2505

Modulation of cytokine/chemokine production in human macrophages by bisphenol A: A comparison to analogues and interactions with genistein

“…Some mechanisms that underpin bisphenol-induced modulation of cytokines/chemokine formation/release have been proposed. One school of thought is that the effects are related to impact of the agents on ER in immune cells: BPA and BPAF each have estrogenic activities for both ER-a and -b; BPS selectively activates ER-a (Li et al 2018). Moreover, BPA, BPS, and BPAF differentially recruit co-regulators to the bisphenol-ER-a complex; this could be one possible reason for differential biological actions induced by these agents.…”

Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway

“…Despite the numerous studies using human ERα structures on molecular dynamics simulations (Celik et al, 2007;Fratev, 2015;Chen et al, 2016;Jereva et al, 2017;Li et al, 2018;Shtaiwi et al, 2018), the ERβ isoform has not yet been analyzed. Furthermore, ERα LBD and ERβ LBD have not been crystallized in mice, even though the resolved rat structure is well known.…”

Impacts of bisphenol A analogues on zebrafish post‐embryonic brain

“…The comparative molecular, physiological and environmental consequences of exposure to BPA analogues are still poorly investigated, albeit an increased number of studies highlight some adverse effects. In vitro, several BPA analogues, including BPS and BPF, act as oestrogen mimics or as anti‐androgens 27‐33 . For example, the molecular mechanisms of action of BPAF and BPS were studied in vitro and showed that BPAF has agonistic activity for both oestrogen receptor (ER)α and ERβ, whereas BPS has ERα‐selective specificity 33 .…”

“…In vitro, several BPA analogues, including BPS and BPF, act as oestrogen mimics or as anti‐androgens 27‐33 . For example, the molecular mechanisms of action of BPAF and BPS were studied in vitro and showed that BPAF has agonistic activity for both oestrogen receptor (ER)α and ERβ, whereas BPS has ERα‐selective specificity 33 . Despite the increasing production and use of BPA analogues, there is still limited knowledge about their potential in vivo toxic and endocrine‐disrupting effects.…”