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Stimulation of Catecholamine Synthesis by Environmental Estrogenic Pollutants

Departments of Pharmacology (N.Y., Y.T., S.U., M.T., M.L., K.T.) and Psychiatry (K.U.), University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan

Address all correspondence and requests for reprints to: Nobuyuki Yanagihara, Ph.D., Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail: yanagin{at}med.uoeh-u.ac.jp.

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 report here the effects of estrogenic pollutants on catecholamine synthesis in bovine 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 d stimulated [¹⁴C]catecholamine synthesis from [¹⁴C]tyrosine and tyrosine hydroxylase activity, an effect that was not inhibited by ICI 182,780, an antagonist of estrogen receptors. Significant effects of p-nonylphenol on [¹⁴C]catecholamine synthesis were observed at 0.1 nM, which is 45 times lower than that of the international regulatory standard (4.5 nM), and the maximum effects were around 10–100 nM. The concentrations (0.1–10 nM) used in the present study are similar to the range observed in rivers in the United States or Europe. On the other hand, short-term treatment of cells with 10 nM p-nonylphenol for 10 min also activated tyrosine hydroxylase, which was suppressed by U0126, an inhibitor of MAPK kinase. Furthermore, treatment of cells with p-nonylphenol for 5 min increased the phospho-p44/42MAPK in a concentration-dependent (1–1000 nM) manner, whereas p-nonylphenol (100 nM, 2 d) enhanced both levels of non-phospho- and phospho-p44/42MAPK. These findings suggest that short-term and long-term treatment of cells with estrogenic pollutants at environmental concentrations stimulates catecholamine synthesis and MAPK through an estrogen receptor-independent pathway.

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