Limits...
Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: role of estrogen receptor β.

Soriano S, Alonso-Magdalena P, García-Arévalo M, Novials A, Muhammed SJ, Salehi A, Gustafsson JA, Quesada I, Nadal A - PLoS ONE (2012)

Bottom Line: Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics.The rapid reduction in the K(ATP) channel activity and the insulinotropic effect was seen in human cells and islets.This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

View Article: PubMed Central - PubMed

Affiliation: Instituto Bioingeniería and CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain.

ABSTRACT
Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ-/- mice to study whether ERβ is involved in the rapid regulation of K(ATP) channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased K(ATP) channel activity, increased glucose-induced [Ca(2+)](i) signals and insulin release in β-cells from WT mice but not in cells from ERβ-/- mice. The rapid reduction in the K(ATP) channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

Show MeSH

Related in: MedlinePlus

Model of BPA action on pancreatic β-cells.In the presence of stimulatory glucose concentrations, low concentrations of BPA rapidly decrease KATP channel activity through ERβ, enhancing glucose-induced [Ca2+]i signals and insulin release. ERα is involved in the regulation of pancreatic insulin biosynthesis in response to BPA. In addition to ERβ, GPR30/GPER1 or another yet unidentified non-classical membrane estrogen receptor may participate in the insulinotropic effect of BPA on pancreatic β-cells. At the moment, this model applies to rodent beta cells. In humans, the receptors involved in the BPA regulation of KATP channel activity and insulin release are still undetermined.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3275611&req=5

pone-0031109-g007: Model of BPA action on pancreatic β-cells.In the presence of stimulatory glucose concentrations, low concentrations of BPA rapidly decrease KATP channel activity through ERβ, enhancing glucose-induced [Ca2+]i signals and insulin release. ERα is involved in the regulation of pancreatic insulin biosynthesis in response to BPA. In addition to ERβ, GPR30/GPER1 or another yet unidentified non-classical membrane estrogen receptor may participate in the insulinotropic effect of BPA on pancreatic β-cells. At the moment, this model applies to rodent beta cells. In humans, the receptors involved in the BPA regulation of KATP channel activity and insulin release are still undetermined.

Mentions: BPA has been considered a weak estrogen because of its low binding affinity to both ERα and ERβ [39], as well as a low transcriptional activity through these ERE binding receptors [40]. ERα and ERβ control nuclear processes that include proliferation, apoptosis and migration exerting opposite effects in different tissues [41]. Nevertheless, it is fully accepted today that estrogen receptors do not work only in this classical manner but they signal as wellfrom extranuclear locations to exert a plethora of actions in different types of cells [37], [42]–[45]. In β-cells non-classical estrogen triggered pathways include regulation of insulin biosynthesis by ERα [24], [25], regulation of glucose stimulated insulin release by ERβ [26], improvement of cell survival by ERα and to a lesser extent by ERβ and GPR30 [37] and control of lipid synthesis by extranuclear ERα [45]. The nonclassical actions of estrogen receptors have main implications in energy balance as demonstrated using genetic rescue of nonclassical ER signalling in ER−/−mice [46]. The use of ERβ−/− mice in the present work and ERα−/− mice in a previous work [24] unequivocally demonstrates that both receptors acting though nonclassical pathways mediate BPA and E2 actions at equal concentrations (Fig. 7). Therefore, BPA cannot be considered a weak estrogen anymore, at least not in β-cells. Nevertheless, why the BPA effects occur at low doses when ERs are located in the extranuclear compartment is a matter of future research. It is possible that BPA binds differently to ERα and ERβ when they are located outside the nucleus. Also the recruitment of co-activators or co-repressors may be completely different [47]. Some of these effects may even be cell-specific. For instance, the insulinotropic action of BPA shown in this work occurs in the presence of a stimulatory glucose concentration of 8 mM. Under this condition most KATP channels are already closed and therefore the membrane resistance is high, so that a small current will elicit the depolarization of the membrane, electrical activity, Ca2+ signals and insulin release. This occurs in β-cells because KATP channels control the resting membrane potential and determine the electrical resistance of the cell [48]. This implies that the closure of a small number of KATP channels by BPA will produce an insulinotropic action.


Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: role of estrogen receptor β.

Soriano S, Alonso-Magdalena P, García-Arévalo M, Novials A, Muhammed SJ, Salehi A, Gustafsson JA, Quesada I, Nadal A - PLoS ONE (2012)

Model of BPA action on pancreatic β-cells.In the presence of stimulatory glucose concentrations, low concentrations of BPA rapidly decrease KATP channel activity through ERβ, enhancing glucose-induced [Ca2+]i signals and insulin release. ERα is involved in the regulation of pancreatic insulin biosynthesis in response to BPA. In addition to ERβ, GPR30/GPER1 or another yet unidentified non-classical membrane estrogen receptor may participate in the insulinotropic effect of BPA on pancreatic β-cells. At the moment, this model applies to rodent beta cells. In humans, the receptors involved in the BPA regulation of KATP channel activity and insulin release are still undetermined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3275611&req=5

pone-0031109-g007: Model of BPA action on pancreatic β-cells.In the presence of stimulatory glucose concentrations, low concentrations of BPA rapidly decrease KATP channel activity through ERβ, enhancing glucose-induced [Ca2+]i signals and insulin release. ERα is involved in the regulation of pancreatic insulin biosynthesis in response to BPA. In addition to ERβ, GPR30/GPER1 or another yet unidentified non-classical membrane estrogen receptor may participate in the insulinotropic effect of BPA on pancreatic β-cells. At the moment, this model applies to rodent beta cells. In humans, the receptors involved in the BPA regulation of KATP channel activity and insulin release are still undetermined.
Mentions: BPA has been considered a weak estrogen because of its low binding affinity to both ERα and ERβ [39], as well as a low transcriptional activity through these ERE binding receptors [40]. ERα and ERβ control nuclear processes that include proliferation, apoptosis and migration exerting opposite effects in different tissues [41]. Nevertheless, it is fully accepted today that estrogen receptors do not work only in this classical manner but they signal as wellfrom extranuclear locations to exert a plethora of actions in different types of cells [37], [42]–[45]. In β-cells non-classical estrogen triggered pathways include regulation of insulin biosynthesis by ERα [24], [25], regulation of glucose stimulated insulin release by ERβ [26], improvement of cell survival by ERα and to a lesser extent by ERβ and GPR30 [37] and control of lipid synthesis by extranuclear ERα [45]. The nonclassical actions of estrogen receptors have main implications in energy balance as demonstrated using genetic rescue of nonclassical ER signalling in ER−/−mice [46]. The use of ERβ−/− mice in the present work and ERα−/− mice in a previous work [24] unequivocally demonstrates that both receptors acting though nonclassical pathways mediate BPA and E2 actions at equal concentrations (Fig. 7). Therefore, BPA cannot be considered a weak estrogen anymore, at least not in β-cells. Nevertheless, why the BPA effects occur at low doses when ERs are located in the extranuclear compartment is a matter of future research. It is possible that BPA binds differently to ERα and ERβ when they are located outside the nucleus. Also the recruitment of co-activators or co-repressors may be completely different [47]. Some of these effects may even be cell-specific. For instance, the insulinotropic action of BPA shown in this work occurs in the presence of a stimulatory glucose concentration of 8 mM. Under this condition most KATP channels are already closed and therefore the membrane resistance is high, so that a small current will elicit the depolarization of the membrane, electrical activity, Ca2+ signals and insulin release. This occurs in β-cells because KATP channels control the resting membrane potential and determine the electrical resistance of the cell [48]. This implies that the closure of a small number of KATP channels by BPA will produce an insulinotropic action.

Bottom Line: Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics.The rapid reduction in the K(ATP) channel activity and the insulinotropic effect was seen in human cells and islets.This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

View Article: PubMed Central - PubMed

Affiliation: Instituto Bioingeniería and CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain.

ABSTRACT
Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ-/- mice to study whether ERβ is involved in the rapid regulation of K(ATP) channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased K(ATP) channel activity, increased glucose-induced [Ca(2+)](i) signals and insulin release in β-cells from WT mice but not in cells from ERβ-/- mice. The rapid reduction in the K(ATP) channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

Show MeSH
Related in: MedlinePlus