G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ER alpha and ER beta in pancreatic beta cells

Autor: Babiloni-Chust I, dos Santos R, Medina-Gali R, Perez-Serna A, Encinar J, Martinez-Pinna J, Gustafsson J, Marroqui L, Nadal A
Rok vydání: 2022
Předmět:
Zdroj: ENVIRONMENT INTERNATIONAL
r-FISABIO. Repositorio Institucional de Producción Científica
instname
ISSN: 0160-4120
Popis: 17 beta-estradiol protects pancreatic beta-cells from apoptosis via the estrogen receptors ER alpha, ER beta and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ER alpha and ER beta, or in dispersed islet cells from ER beta knockout (BERKO) mice. However, the ER alpha and ER beta agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ER alpha and ER beta form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ER alpha and ER beta as well as GPER activation by G1 decreased ER alpha beta heterodimers. We propose that ER alpha beta heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ER alpha beta heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.
Databáze: OpenAIRE
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