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Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
Address all correspondence and requests for reprints to: Scott M. Belcher, Ph.D., Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, P.O. Box 670575, Cincinnati, Ohio 45267-0575. E-mail: scott.belcher{at}uc.edu.
In addition to regulating estrogen receptor-dependent gene expression, 17ß-estradiol (E2) can directly influence intracellular signaling. In primary cultured cerebellar neurons, E2 was previously shown to regulate growth and oncotic cell death via rapid stimulation of ERK1/2 signaling. Here we show that ERK1/2 signaling in the cerebellum of neonatal and mature rats was rapidly responsive to E2 and during development to the environmental estrogen bisphenol A (BPA). In vivo dose-response analysis for each estrogenic compound was performed by brief (6-min) intracerebellar injection, followed by rapid fixation and phosphorylation-state-specific immunohistochemistry to quantitatively characterize changes in activated ERK1/2 (pERK) immunopositive cell numbers. Beginning on postnatal d 8, E2 significantly influenced the number of pERK-positive cells in a cell-specific manner that was dependent on concentration and age but not sex. In cerebellar granule cells on postnatal d 10, E2 or BPA increased pERK-positive cell numbers at low doses (10–12 to 10–10 M) and at higher (10–7 to 10–6 M) concentrations. Intermediate concentrations of either estrogenic compound did not modify basal ERK signaling. Rapid E2-induced increases in pERK immunoreactivity were specific to the ERK1/2 pathway as demonstrated by coinjection of the mitogen-activated, ERK-activating kinase (MEK)1/2 inhibitor U0126. Coadministration of BPA (10–12 to 10–10 M) with 10–10 M E2 dose-dependently inhibited rapid E2-induced ERK1/2 activation in developing cerebellar neurons. The ability of BPA to act as a highly potent E2 mimetic and to also disrupt the rapid actions of E2 at very low concentrations during cerebellar development highlights the potential low-dose impact of xenoestrogens on the developing brain.
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