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Sci Rep. 2017 Sep 18;7(1):11770. doi: 10.1038/s41598-017-11995-3.

Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on ca2+ entry in mouse pancreatic β-cells.

Author information

1
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Institute of Bioenginering, Miguel Hernández University of Elche, Elche, Alicante, Spain.
2
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
3
Department of Cell Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA.
4
Department of Biosciences and Nutrition, Karolinska Institut, Huddinge, Sweden.
5
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Institute of Bioenginering, Miguel Hernández University of Elche, Elche, Alicante, Spain. nadal@umh.es.

Abstract

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 Ca2+ entry in an NMDR manner. Low doses decreased plasma membrane Ca2+ currents after downregulation of Cav2.3 ion channel expression, in a process involving ERβ. High doses decreased Ca2+ currents through an ERβ-mediated mechanism and simultaneously increased Ca2+ currents via oestrogen receptor ERα. The outcome of both molecular mechanisms explains the NMDR relationship between BPA and Ca2+ entry in β-cells.

PMID:
28924161
PMCID:
PMC5603522
DOI:
10.1038/s41598-017-11995-3
[Indexed for MEDLINE]
Free PMC Article

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