Effects of environmental estrogenic pollutants on cellular functions in the noradrenergic neurons and search for their receptors

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Environmental estrogenic pollutants are compounds that have been shown to have estrogenic effects on fetal development and reproductive systems. Less attention, however, has been paid to their influence on neuronal functions. We have examined the effects of estrogenic pollutants on catecholamine synthesis in adrenal medullary cells used as a model system of noradrenergic neurons. Treatment of cultured bovine adrenal medullary cells with p-nonylphenol and bisphenol A at 10 nM for 3 days stimulated ^<14>C-catecholamine synthesis from [^<14>C]tyrosine and tyrosine hydroxylase activity, an effect that was not inhibited by ICI 182,780, an inhibitor of estrogen receptors. Significant effects of p-nonylphenol on ^<14>C-catecholamine synthesis were observed at 0.1 nM that is 50 times lower than that of the international regulatory standard (5 nM) and the maximum effects were around at 10 nM. Short-term treatment of cells with 10 nM p-nonylphenol for 10 min also activated tyrosine hydroxylase, … More which was suppressed by U0126, an inhibitor of mitogen-activated protein kinase (MAPK) kinase. Furthermore, treatment of cells with p-nonylphenol for 5 min increased the phospho-p44/42MAPK in a concentration (1 - 1000 nM)-dependent manner.Incubation of adrenal medullary cells with 17β-estradiol(E_2) (0.3-100 nM) or membrane-impermeable E_2-bovine serum albumin (100 nM) also acutely increased ^<14>C-catecholamine synthesis from [^<14>C]tyrosine. The plasma membrane isolated from the gland showed two classes of specific binding sites of [^3H] E_2 with apparent Kds of 3.2 and 106 nM and Bmaxs of 0.44 and 8.5 pmol/mg protein, respectively. The high-affinity binding of [^3H] E_2 was most strongly inhibited by E_2 and phytoestrogens, and to lesser extents by other steroid hormones, while it was enhanced by ICI182,780 and environmental estrogenic pollutants.These findings suggest that E_2 and environmental estrogenic pollutants acutely stimulates catecholamine synthesis via activation of p44/42MAPK through unique estrogen receptors in the plasma membrane of bovine adrenal medulla. Less