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      Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca 2+ Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans

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          Abstract

          Glucagon, secreted from pancreatic α-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 ([Ca 2+] i) oscillations in α-cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol (E 2) conjugated to horseradish peroxidase (E-HRP). Competition studies using E-HRP binding in immunocytochemically identified α-cells indicate that 17β-E 2, BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the classical ER. The effects triggered by BPA, DES, and E 2 are blocked by the Gα i- and Gα 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 E 2, BPA, and DES in pancreatic α-cells may explain some of the effects elicited by endocrine disruptors in the metabolism of glucose and lipid.

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          Most cited references73

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          Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.

          The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
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            A review of the environmental fate, effects, and exposures of bisphenol A.

            Bisphenol A (CAS 85-05-7) may be released into the environment through its use and handling, and permitted discharges. BPA is moderately soluble (120 to 300 mg/L at pH 7), may adsorb to sediment (Koc 314 to 1524), has low volatility, and is not persistent based on its rapid biodegradation in acclimated wastewater treatment plants and receiving waters (half-lives 2.5 to 4 days). BPA is "slightly to moderately" toxic (algal EC50 of 1000 micrograms/L) and has low potential for bioaccumulation in aquatic organisms (BCFs 5 to 68). The chronic NOEC for Daphnia magna is > 3146 micrograms/L. Surface water concentrations are at least one to several orders of magnitude lower than chronic effects, with most levels nondetected.
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              Glucagon and regulation of glucose metabolism.

              As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also glucagon. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, glucagon and glucagon receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                August 2005
                18 May 2005
                : 113
                : 8
                : 969-977
                Affiliations
                Institute of Bioengineering, Miguel Hernández University, Sant Joan d’Alacant, Alicante, Spain
                Author notes
                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.

                The authors declare they have no competing financial interests.

                Article
                ehp0113-000969
                10.1289/ehp.8002
                1280335
                16079065
                9f358ab1-a166-4d4c-869d-892bf847ec96
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 3 February 2005
                : 18 May 2005
                Categories
                Research

                Public health
                environmental estrogens,endocrine disruptors,islets of langerhans,estrogen receptors,cgmp,nongenomic,second messengers,glucagon

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