G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERα and ERβ in pancreatic beta cells. (June 2022)

• Record Type: Journal Article
• Authors: Babiloni-Chust, Ignacio; dos Santos, Reinaldo S.; Medina-Gali, Regla M.; Perez-Serna, Atenea A.; Encinar, José-Antonio; Martinez-Pinna, Juan; Gustafsson, Jan-Ake; Marroqui, Laura; Nadal, Angel
• Is Part Of: Environment international. Volume 164(2022)
• Publication Date: 2022-06
• Subjects: Apoptosis -- Bisphenol-A -- Endocrine disruptors -- GPER/GPR30 -- Heterodimers -- 17β-estradiol -- Estrogen receptors; BERKO Estrogen receptor β knockout -- BPA Bisphenol-A -- DCF 2′, 7′-dichlorofluorescein diacetate -- E2 17β-estradiol -- ER Estrogen receptor -- ERα Estrogen receptor α -- ERβ Estrogen receptor β -- GPER G protein-coupled estrogen receptor -- LBD Ligand binding domain -- MPP Methylpiperidinopyrazole -- PHTPP 4-(2-phenyl-5, 7-bis(trifluoromethyl)pyrazolo[1, 5-a]pyrimidin-3-yl)phenol -- PLA Proximity ligand assay -- ROS Reactive oxygen species -- siRNA Small interfering RNA; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2022.107250
• Languages: English
• ISSNs: 0160-4120

Abstract

Graphical abstract: Highlights: Gene silencing of ERα, ERβ and GPER increased apoptosis under basal conditions. GPER activation by G1 and BPA triggered apoptosis via crosstalk with ERα and ERβ. BPA decreased ERαβ heterodimers, which was associated with increased apoptosis. This novel molecular-initiating event underlies the pro-apoptotic effect of BPA. Abstract: 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. However, 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 dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as 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 decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.