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

Babiloni-Chust, I.; Dos Santos, R. S.; Medina-Gali, R. M.; Perez-Serna, A. A.; Encinar, J. A.; Martinez-Pinna, J.; Gustafsson, J.-A.; Marroqui, L.; Nadal, A.

doi:10.1101/2022.01.31.478472

bioRxiv · 10.1101/2022.01.31.478472

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

Babiloni-Chust, I.·Dos Santos, R. S.·Medina-Gali, R. M.·Perez-Serna, A. A.·Encinar, J. A.·Martinez-Pinna, J.·Gustafsson, J.-A.·Marroqui, L.·Nadal, A.

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Abstract

17{beta}-estradiol protects pancreatic {beta}-cells from apoptosis via the estrogen receptors ER, 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 and ER{beta}, or in dispersed islet cells from ER{beta} knockout (BERKO) mice. Yet, the ER and ER{beta} agonists, PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ER and ER{beta} form homodimers and heterodimers. Molecular dynamic simulations together with proximity ligand assay and coimmunoprecipitation experiments indicated that the interaction of BPA with ER and ER{beta} as well as the GPER activation by G1 decreased ER{beta} heterodimers. We propose that ER{beta} heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decrease in ER{beta} heterodimers leads to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors. HighlightsO_LIPharmacological blockade and gene silencing of estrogen receptors ER, ER{beta} and GPER indicate that they are antiapoptotic in basal conditions. C_LIO_LIGPER activation by G1 and BPA triggered apoptosis via a crosstalk with ER and ER{beta}. C_LIO_LIBPA interaction with ER and ER{beta} as well as GPER activation decreased ER{beta} heterodimers, which was associated to increased apoptosis. C_LIO_LIThis pathway represents a novel molecular initiating event underlying the pro-apoptotic effect of BPA C_LIO_LIThe EndoC-{beta}H1 cell line may be a valid model of human {beta}-cells for identifying diabetogenic pollutants. C_LI

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Babiloni-Chust, I., Dos Santos, R. S., Medina-Gali, R. M., Perez-Serna, A. A., Encinar, J. A., Martinez-Pinna, J., Gustafsson, J.-A., Marroqui, L., Nadal, A.. 2022-02-01. G protein-coupled oestrogen receptor activation by Bisphenol-A disrupts protection from apoptosis conferred by oestrogen receptors ERα and ERβ in pancreatic beta cells. https://doi.org/10.1101/2022.01.31.478472

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