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Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca²⁺ Signals in Pancreatic -Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans

Paloma Alonso-Magdalena, Ouahiba Laribi,* Ana B. Ropero,** Esther Fuentes, Cristina Ripoll, Bernat Soria, and Angel Nadal

Institute of Bioengineering, Miguel Hernández University, Sant Joan d'Alacant, Alicante, Spain

Abstract
Glucagon, secreted from pancreatic -cells integrated within the islets of Langerhans, is involved in the regulation of glucose metabolism by enhancing the synthesis and mobilization of glucose in the liver. In addition, it has other extrahepatic effects ranging from lipolysis in adipose tissue to the control of satiety in the central nervous system. In this article, we show that the endocrine disruptors bisphenol A (BPA) and diethylstilbestrol (DES) , at a concentration of 10^-9 M, suppressed low-glucose-induced intracellular calcium ion ([Ca²⁺]_i) oscillations in -cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol (E₂) conjugated to horseradish peroxidase (E-HRP) . Competition studies using E-HRP binding in immunocytochemically identified -cells indicate that 17β-E₂, BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the classical ER. The effects triggered by BPA, DES, and E₂ are blocked by the Gi- and G_o-protein inhibitor pertussis toxin, by the guanylate cyclase-specific inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. The effects are reproduced by 8-bromo-guanosine 3',5'-cyclic monophosphate and suppressed in the presence of the cGMP-dependent protein kinase inhibitor KT-5823. The action of E₂, BPA, and DES in pancreatic -cells may explain some of the effects elicited by endocrine disruptors in the metabolism of glucose and lipid. Key words: cGMP, endocrine disruptors, environmental estrogens, estrogen receptors, glucagon, islets of Langerhans, nongenomic, second messengers. Environ Health Perspect 113:969-977 (2005) . doi:10.1289/ehp.8002 available via http://dx.doi.org/ [Online 18 May 2005]

Address correspondence to A. Nadal, Institute of Bioengineering, Miguel Hernández University, San Juan Campus, Carretera Alicante-Valencia Km 87, Sant Joan d'Alacant 03550, Alicante, Spain. Telephone: 34-96-5919535. Fax: 34-96-5919547. E-mail: nadal@umh.es

*Current address: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. **Current address: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

We thank B. Fernández (Generalitat Valenciana) for excellent technical assistance.

This study was supported by the Spanish Ministry of Education and Science grant BFI2002-01469 and Instituto de Salud Carlos III grants RCMN (C03/08) and 03/0178. P.A.-M. has a fellowship from the Ministry of Education and Science, O.L. has a fellowship from the Spanish Ministry of Foreign Affairs, and A.B.R. has a fellowship from the Spanish Ministry of Science and Technology.

The authors declare they have no competing financial interests.

Received 3 February 2005 ; accepted 18 May 2005.