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.

中文翻译：

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双酚S和双酚F通过雌激素受体ERβ介导的途径改变小鼠胰腺β细胞离子通道的表达和活性以及胰岛素释放

双酚S（BPS）和双酚F（BPF）是当前的双酚A（BPA）替代品。在这里，我们使用野生型（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减少ATP敏感性K +（KATP）通道活性。同样，用BPS或BPF处理48小时可提高胰岛素释放，并降低野生型小鼠β细胞中几个离子通道亚基的表达，但在BERKO小鼠的细胞中未观察到作用。PaPE-1是一种设计为优先触发核外启动的ER途径的配体，它模仿了双酚的作用，暗示了核外启动的ERβ途径的参与。分子动力学模拟表明不同双酚和PaPE-1之间的ERβ配体结合域二聚体稳定和溶剂化自由能的差异。我们的数据表明一种涉及ERβ的作用方式，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善双酚的危害识别。