Pancreatic effects of EDCs: low doses can impair glucagon secretion.

Endocrine-disrupting chemicals (EDCs) mimic naturally occurring hormones such as estrogen by occupying hormone receptors and triggering a reaction in the body. Interactions of EDCs with the classical (nuclear) estrogen receptors ER-[alpha] and ER-[beta] have been well characterized, and there is also growing knowledge regarding interactions with nonclassical receptors (found elsewhere, as on the cell membrane). Both classical and nonclassical estrogen receptors occur throughout the body, reflecting the many roles played by estrogen in regulating the body's functions. This widespread presence also translates to myriad ways that EDCs could potentially interfere with health. New research now suggests that pancreatic cells are affected by EDC exposure, with potential health consequences [EHP 113:969-977].

Although the pancreas might seem an unlikely estrogen target, it bears classical and nonclassical receptors on both [alpha]- and [beta]-cells in the islet of Langerhans. These cells secrete glucagon and insulin, respectively, hormones that regulate blood glucose levels, among other functions. In [alpha]-cells, low blood glucose causes increased calcium oscillations--or fluctuations in intracellular calcium concentrations--via a transmembrane channel; these oscillations trigger glucagon secretion.

Glucagon regulates functions in fat tissue and in the liver, brain, kidney, intestine, and pancreas. The primary role of glucagon is to enhance glucose synthesis and release in the liver. Secondary roles include increased fatty acid release from fat cells and appetite control in the central nervous system. These responses to low glucose can be suppressed by the endogenous estrogen 17[beta]-estradiol and, as demonstrated in the current report, by EDCs as well.

The research team focused on two EDCs: bisphenol A, a component of such products as polycarbonate plastic and dental sealants, and diethylstilbestrol, a synthetic estrogen used from the 1940s to the 1970s to prevent miscarriage. Based on previous research, the researchers hypothesized that 17[beta]-estradiol and the EDCs would bind to nonclassical estrogen receptors on the membrane of glucagon-producing [alpha]-cells and activate a sequence of secondary messengers within the cell, leading to control of the transmembrane calcium channel and related calcium oscillations.

To test the hypothesis, they examined freshly isolated mouse pancreatic islets and subjected samples to physiological assays. Competitive binding assays indicated that 17[beta]-estradiol, bisphenol A, and diethylstilbestrol shared a common membrane-binding site. This binding was unaffected in competitive assays using the pure antiestrogen ICI182,780, which inhibits only classical ER-mediated effects. This result indicated that the common binding site was a nonclassical membrane estrogen receptor. Immunocytochemical assays confirmed that 17[beta]-estradiol and the EDCs bound to glucagon-producing [alpha]-cells.

Further assays of bisphenol A alone used compounds known to inhibit steps along the suspected pathway. These assays provided evidence that 17[beta]-estradiol and bisphenol A affected the sequence of cellular reactions that ultimately regulates calcium oscillations. These oscillations were tracked by laser scanning confocal microscopy.

The researchers note that there is some debate regarding the EDC concentrations necessary to produce biological effects in humans and animals. Their study indicates that EDC doses in the nanomolar range are sufficient to suppress calcium oscillations, potentially affecting secretion of glucagon. The possible consequences of this suppression could include changes in glucose and lipid metabolism and reduced use of stored glucose and fat, which could contribute to obesity.