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

“…Conversely, BPA shows rapid structural rearrangements for both homodimers and heterodimers (Supplementary Fig. 8), a behavior previously showed for monomers (Li et al, 2018;Marroqui et al, 2021). This suggests a less stable binding of BPA compared to E2 for the three configurations of dimers.…”

“…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 homoand 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).…”

Bisphenol S Impairs Invasion and Proliferation of Extravillous Trophoblasts Cells by Interfering with Epidermal Growth Factor Receptor Signaling

“…For instance, cell-to-cell communication that involves Notch signaling is crucial for the formation of complex multicellular structures such as blood vessel networks [ 60 ]. Since the estrogen receptor and EGFR pathways can regulate Notch signaling in opposite directions [ 61 ], the effect the BPS and EGF mixture has on inhibition of tube formation may stem from an inhibition of the EGFR pathway associated with an induction of the estrogen receptor pathway [ 62 ]. However, whether in vivo exposure to BPS alters angiogenesis during placental development remains to be determined.…”

Human Pluripotent Stem Cells: A Unique Tool for Toxicity Testing in Pancreatic Progenitor and Endocrine Cells

“…For example, BPA, a non-persistent additive commonly used in plastic products, acutely increases insulin secretion in mouse and human islets via inhibition of K ATP channels and increased Ca 2+ signaling (75), whereas longer-term BPA exposure inhibits Ca 2+ entry and reduces insulin secretion (76). Newer BPA-replacement chemicals, BPS and BPF, also disrupt mouse b-cell function (77). Exposure to POPs, including organochlorine pesticides and a PCB mixture, directly inhibited insulin secretion in a rat b-cell line (INS-1E cells) (30).…”