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

Abstract

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.

G protein-coupled estrogen receptor activation by Bisphenol-A disrupts protection from apoptosis conferred by estrogen receptors ERα and ERβ in pancreatic beta cells

“…6g-i). Of note, positive values indicate strong ligand-protein binding (Marroqui et al, 2021). E2 binding to both homodimer cavities, LBD-ERαα (Fig.…”

“…Bisphenol-A (BPA), which is used as a model of endocrine disrupting chemical that alters insulin secretion and insulin sensitivity in mice (Alonso-Magdalena et al, 2010, 2006), has been implicated in the etiology of diabetes (Alonso-Magdalena et al, 2011; Sargis and Simmons, 2019). At concentrations similar to those found in human blood (Vandenberg et al, 2010), BPA increases pancreatic insulin content via ERα (Alonso-Magdalena et al, 2008) and regulates ion channel expression and function as well as augments insulin release in an ERβ-mediated manner (Marroqui et al, 2021; Martinez-Pinna et al, 2019; Soriano et al, 2012). In INS-1 cells and mouse dispersed islet cells, BPA induces mitochondrial dysfunction, ROS production and NF-κB activation, which culminates in beta cell apoptosis (Carchia et al, 2015; Lin et al, 2013).…”

“…More than 300 human ERα-ligand-binding domain (LBD) (UniProt code: P03372) and 32 human ERβ-LBD (UniProt code: Q92731) structures were resolved from cryptographic data. As these structures contained unresolved residues in mobile regions of the protein that diffracted poorly, the lost amino acids were reconstructed after generation of a homology model at the Swiss-Model server (Biasini et al, 2014; Marroqui et al, 2021). After unresolved gaps elimination, models for the hERα-LBD monomer (Protein Data Bank entry 5DXE as template) and the hERβ-LBD monomer (Protein Data Bank entry 3OLS as template) were generated.…”

“…From these monomeric structures homo- and heterodimers were reconstructed using GRAMM-X server (Tovchigrechko and Vakser, 2006). E2 and BPA molecular docking simulations within the cavity of each LBD were performed using the YASARA structure software (version 20.12.24) (Marroqui et al, 2021). Molecular dynamics simulations on the structures with the best docking calculations were performed with YASARA structure software (version 20.10.24) (Marroqui et al, 2021).…”

Screening of Relevant Metabolism-Disrupting Chemicals on Pancreatic β-Cells: Evaluation of Murine and Human in Vitro Models

“…To date, only one study has been published exploring BPS action. This study showed that mouse islets of Langerhans treated with 1 nM and 1 μM BPS exhibited enhanced insulin release compared to controls [37].…”