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

• Published in: bioRxiv
• Main Authors: Babiloni-Chust, Ignacio, Reinaldo Sousa Dos Santos, Medina-Gali, Regla Maria, Perez-Serna, Atenea Alexandra, Encinar, Jose Antonio, Martinez-Pinna, Juan, Gustafsson, Jan-Ake, Marroqui, Laura, Nadal, Angel
• Format: Paper Publication
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.02.2022; Cold Spring Harbor Laboratory
• Edition: 1.2
• Subjects: 17β-Estradiol; Agonists; Apoptosis; Beta cells; Bisphenol A; Cell viability; Endocrine disruptors; Estrogen receptors; Estrogens; Islet cells; Pancreas; Physiology; Receptor mechanisms; Xenoestrogens; Endocrine disruptors; Bisphenol-A; Heterodimers; Estrogen receptors; 17β-estradiol; GPER/GPR30; Apoptosis
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2022.01.31.478472

17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ 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 ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. Yet, the ERα and ERβ agonists, PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamic simulations together with proximity ligand assay and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as the GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decrease in ERαβ heterodimers leads to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors. Competing Interest Statement The authors have declared no competing interest.