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The Endocrine-Disrupting Compound, Nonylphenol, Inhibits Neurotrophin-Dependent Neurite Outgrowth

Departments of Physiology (C.L.B., D.M.P., C.R.S., L.P.H.) and Biochemistry (E.Y.B.), Dartmouth Medical School, Hanover, New Hampshire 03755; and Department of Neurosciences (T.J.H., H.L., M.J.H.), Medical University of Ohio, Toledo, Ohio 43614

Address all correspondence and requests for reprints to: Leslie P. Henderson, Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755. E-mail: Leslie.Henderson{at}Dartmouth.edu.

Endocrine-disrupting compounds (EDCs) may interfere with neuronal development due to high levels of accumulation in biological tissue and potentially aberrant steroid signaling. Treatment of dissociated embryonic Xenopus spinal cord neurons with the EDC, nonylphenol (NP), did not alter cell survival or neurite outgrowth but inhibited neurotrophin-induced neurite outgrowth, effects that were recapitulated by treatment with comparable concentrations of 17ß-estradiol (E₂) and ß-estradiol 6-(O-carboxy-methyl)oxime: BSA (E₂-BSA), but not a synthetic androgen. Effects of NP were not inhibited by the nuclear estrogen receptor antagonist, ICI 182,780, but were inhibited by the G protein antagonist, pertussis toxin. Nerve growth factor (NGF)-induced neurite outgrowth in Xenopus neurons was shown to require MAPK signaling. NP did not affect TrkA expression, MAPK signaling, or phosphatidylinositol 3' kinase-Akt-glycogen synthase kinase 3ß (PI3K-Akt-GSK3ß) signaling in Xenopus. The ability of NP to inhibit NGF-induced neurite outgrowth without altering survival was recapitulated in the rat pheochromocytoma (PC12) cell line. As with Xenopus neurons, the inhibitory actions of NP in PC12 cells were not antagonized by ICI 182,780 and did not involve alterations in signaling along either the MAPK or PI3K-Akt-GSK3ß pathways. NP did significantly inhibit the ability of NGF to increase protein kinase A activity in this cell line. These data have important implications with respect to potentially deleterious effects of NP exposure during early neural development and highlight the fact that bioaccumulation of EDCs, such as NP, may elicit very disparate effects along divergent signaling pathways than those that arise from the actions of physiological levels of endogenous estrogens.