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⁺ (K_ATP) 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.

双酚-S (BPS) 和双酚-F (BPF) 是目前双酚-A (BPA) 的替代品。在这里，我们使用来自野生型（WT）和雌激素受体β（ERβ）敲除（BERKO）小鼠的胰腺β细胞来研究BPS和BPF对胰岛素分泌的影响，以及参与β细胞的离子通道的表达和活性。功能。BPS 或 BPF 迅速增加胰岛素释放并降低 ATP 敏感性 K ⁺ (K _ATP) 渠道活动。类似地，用 BPS 或 BPF 处理 48 小时可增强 WT 小鼠 β 细胞中的胰岛素释放并降低几个离子通道亚基的表达，但在 BERKO 小鼠的细胞中未观察到任何影响。PaPE-1 是一种旨在优先触发核外启动的 ER 通路的配体，它模拟了双酚的作用，表明参与了核外启动的 ERβ 通路。分子动力学模拟表明不同双酚和 PaPE-1 在 ERβ 配体结合域二聚体稳定性和溶剂化自由能方面存在差异。我们的数据表明了一种涉及 ERβ 的作用模式，其激活改变了 β 细胞中的三个关键细胞事件，即离子通道表达和活性，以及​​胰岛素释放。这些结果可能有助于改进双酚的危害识别。