Journal Article

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

Korach, Kenneth S., Tyler Ramsey, J., Burns, Katherine A., van Beuningen, Rinie, Houtman, René, Teng, Christina T., Coons, Laurel A., Li, Yin, Perera, Lalith, Pelch, Katherine E.

2018

Overview

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. 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. 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. 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. 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.

• Publisher: National Institute of Environmental Health Sciences,Environmental Health Perspectives
• Subject: Benzhydryl Compounds - toxicity / Binding / Biological activity / Bisphenol A / Cancer / Cell culture / Cell Line, Tumor / Computer simulation / Coordination compounds / DNA microarrays / Endocrine disruptors / Endocrine Disruptors - metabolism / Endocrine Disruptors - toxicity / Endocrine system / Estrogen Receptor alpha - drug effects / Estrogen Receptor alpha - metabolism / Estrogen Receptor beta - drug effects / Estrogen Receptor beta - metabolism / Estrogen receptors / Estrogens / Estrogens - pharmacology / Experiments / Gene expression / Humans / In vitro methods and tests / Ligands / Microarray Analysis / Molecular dynamics / Molecular Dynamics Simulation / Molecular modelling / Organic chemistry / Phenols / Phenols - toxicity / Physiological effects / Plasmids / Polymerase chain reaction / Proteins / Risk factors / RNA polymerase / Sulfones - toxicity / Toxicity / Transcription activation / Xenoestrogens