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Submitted on May 10, 2005
Accepted on August 16, 2005
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575
* To whom correspondence should be addressed. E-mail: scott.belcher{at}uc.edu.
In addition to regulating estrogen receptor-dependent gene expression, 17
-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 extracellular regulated kinase 1 and 2 (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 day 8 (P8), 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 P10, E2 or BPA increased pERK-positive cell numbers at low-doses (10-12-10-10M) and at higher (10-7-10-6M) 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 co-injection of the MEK1/2 inhibitor U0126. Co-administration of BPA (10-12 to 10-10M) with 10-10M 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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