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Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells

In regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma “the dose makes the poison”. Many endocrine disrupting chemicals,...

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Autores principales: Villar-Pazos, Sabrina, Martinez-Pinna, Juan, Castellano-Muñoz, Manuel, Alonso-Magdalena, Paloma, Marroqui, Laura, Quesada, Ivan, Gustafsson, Jan-Ake, Nadal, Angel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603522/
https://www.ncbi.nlm.nih.gov/pubmed/28924161
http://dx.doi.org/10.1038/s41598-017-11995-3
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author Villar-Pazos, Sabrina
Martinez-Pinna, Juan
Castellano-Muñoz, Manuel
Alonso-Magdalena, Paloma
Marroqui, Laura
Quesada, Ivan
Gustafsson, Jan-Ake
Nadal, Angel
author_facet Villar-Pazos, Sabrina
Martinez-Pinna, Juan
Castellano-Muñoz, Manuel
Alonso-Magdalena, Paloma
Marroqui, Laura
Quesada, Ivan
Gustafsson, Jan-Ake
Nadal, Angel
author_sort Villar-Pazos, Sabrina
collection PubMed
description In regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma “the dose makes the poison”. Many endocrine disrupting chemicals, including bisphenol-A (BPA), induce non-monotonic dose response (NMDR) relationships, which are unconventional and have tremendous implications in risk assessment. Although several molecular mechanisms have been proposed to explain NMDR relationships, they are largely undemonstrated. Using mouse pancreatic β-cells from wild-type and oestrogen receptor ERβ−/− mice, we found that exposure to increasing doses of BPA affected Ca(2+) entry in an NMDR manner. Low doses decreased plasma membrane Ca(2+) currents after downregulation of Cav2.3 ion channel expression, in a process involving ERβ. High doses decreased Ca(2+) currents through an ERβ-mediated mechanism and simultaneously increased Ca(2+) currents via oestrogen receptor ERα. The outcome of both molecular mechanisms explains the NMDR relationship between BPA and Ca(2+) entry in β-cells.
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spelling pubmed-56035222017-09-20 Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells Villar-Pazos, Sabrina Martinez-Pinna, Juan Castellano-Muñoz, Manuel Alonso-Magdalena, Paloma Marroqui, Laura Quesada, Ivan Gustafsson, Jan-Ake Nadal, Angel Sci Rep Article In regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma “the dose makes the poison”. Many endocrine disrupting chemicals, including bisphenol-A (BPA), induce non-monotonic dose response (NMDR) relationships, which are unconventional and have tremendous implications in risk assessment. Although several molecular mechanisms have been proposed to explain NMDR relationships, they are largely undemonstrated. Using mouse pancreatic β-cells from wild-type and oestrogen receptor ERβ−/− mice, we found that exposure to increasing doses of BPA affected Ca(2+) entry in an NMDR manner. Low doses decreased plasma membrane Ca(2+) currents after downregulation of Cav2.3 ion channel expression, in a process involving ERβ. High doses decreased Ca(2+) currents through an ERβ-mediated mechanism and simultaneously increased Ca(2+) currents via oestrogen receptor ERα. The outcome of both molecular mechanisms explains the NMDR relationship between BPA and Ca(2+) entry in β-cells. Nature Publishing Group UK 2017-09-18 /pmc/articles/PMC5603522/ /pubmed/28924161 http://dx.doi.org/10.1038/s41598-017-11995-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Villar-Pazos, Sabrina
Martinez-Pinna, Juan
Castellano-Muñoz, Manuel
Alonso-Magdalena, Paloma
Marroqui, Laura
Quesada, Ivan
Gustafsson, Jan-Ake
Nadal, Angel
Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title_full Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title_fullStr Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title_full_unstemmed Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title_short Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca(2+) entry in mouse pancreatic β-cells
title_sort molecular mechanisms involved in the non-monotonic effect of bisphenol-a on ca(2+) entry in mouse pancreatic β-cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603522/
https://www.ncbi.nlm.nih.gov/pubmed/28924161
http://dx.doi.org/10.1038/s41598-017-11995-3
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