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
Por:
Babiloni-Chust, I, dos Santos, R, Medina-Gali, R, Perez-Serna, A, Encinar, J, Martinez-Pinna, J, Gustafsson, J, Marroqui, L and Nadal, A
Publicada:
1 jun 2022
Ahead of Print:
1 abr 2022
Categoría:
Environmental science (miscellaneous)
Resumen:
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.
Filiaciones:
Babiloni-Chust, I:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
dos Santos, R:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Medina-Gali, R:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Perez-Serna, A:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Martinez-Pinna, J:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Univ Alicante, Dept Fisiol Genet & Microbiol, Alicante, Spain
Gustafsson, J:
Univ Houston, Dept Cell Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA
Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden
Marroqui, L:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Nadal, A:
Univ Miguel Hernandez Elche, Inst Invest Desarrollo & Innovat Biotecnol Sanita, Alicante 03202, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
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