Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

Glucagon, secreted from pancreatic [alpha]-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.sup.-9] M, suppressed low-glucose--induced intracellular calcium ion ([[[Ca.sup.2+]].sub.i]) oscillations in [alpha]-cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol ([E.sub.2]) conjugated to horseradish peroxidase (E-HRP). Competition studies using E-HRP binding in immunocytochemically identified [alpha]-cells indicate that 17[beta]-[E.sub.2], BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the dassical ER. The effects triggered by BPA, DES, and [E.sub.2] are blocked by the G[alpha]i- and G[[alpha].sub.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.sub.2], BPA, and DES in pancreatic [alpha]-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. doi:10.1289/ehp.8002 available via http://dx.doi.org/[Online 18 May 2005]

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Glucagon is a 29-amino acid pancreatic hormone that is secreted from the pancreatic [alpha]-cells into the portal blood supply in response to hypoglycemia, acting as the counter-regulatory hormone to insulin. Its main biologic effect is the regulation of glucose metabolism by enhancing the synthesis and mobilization of glucose in the liver. There is solid evidence demonstrating that the inhibition of glucagon signaling in vivo leads to a reduction of plasma glucose (Jiang and Zhang 2003). In addition, glucagon has many extrahepatic effects, such as the increase of lipolysis in adipose tissue, a positive inotropic effect in the heart, a role in the satiety control in the central nervous system, and the regulation of the glomerular filtration rate (Berne and Levy 1993). In the islets of Langerhans, it participates in the regulation of intraislet hormone, insulin, somatostatin, and glucagon secretion (Gromada et al. 1997a; Ma et al. 2005). When insulin secretion from [beta]-cells is impaired, diabetes mellitus develops. In this pathology, the normal physiologic suppression of glucagon secretion from pancreatic [alpha]-cells in response to elevated plasma glucose is lost (Unger and Orci 1981a, 1981b). A concomitant decrease in early insulin secretion in response to oral glucose is also observed. These combined defects alter the insulin-to-glucagon ratio, leading to a failure of the normal suppression of endogenous glucose production that occurs after ingestion of oral glucose (Gerich 1997). This contributes to the elevation of glucose levels in plasma in individuals with impaired glucose tolerance or diabetes.

Despite the great importance of [alpha]-cells, little is known about the stimulus secretion coupling and its regulation by other hormones and neurotransmitters. This is partly due to the scarcity of islet tissue and small proportion of [beta]-cells compared with insulin-releasing [alpha]-cells. [alpha]-Cells contain a specific set of ion channels, including a voltage-dependent [Na.sup.+] channel, responsible for their electrical activity (Gopel et al. …

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