Bisphenol A (BPA) a chemical used in
milk containers, water pipes and dental sealants
found to disrupt the effects of estrogen in developing brains:
Two papers 1dec2005
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Ontogeny of Rapid Estrogen-Mediated Extracellular Signal-Regulated Kinase Signaling in the Rat Cerebellar Cortex: Potent Nongenomic Agonist and Endocrine Disrupting Activity of the Xenoestrogen Bisphenol A

A Zsarnovszky et al / Endocrinology v.146, n.12 1dec2005

Attila Zsarnovszky, Hoa H. Le, Hong-Sheng Wang and Scott M. Belcher

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@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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Rapid Estrogenic Regulation of Extracellular Signal- Regulated Kinase 1/2 Signaling in Cerebellar Granule Cells Involves a G Protein- and Protein Kinase A-Dependent Mechanism and Intracellular Activation of Protein Phosphatase 2A

S.M. BELCHER et al / Endocrinology v.146, n.12 1dec2005

Scott M. Belcher, Hoa H. Le, Lynda Spurling and Jeremy K. Wong

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@uc.edu .

In neonatal rat cerebellar neurons, 17ß-estradiol (E₂) rapidly stimulates ERK1/2 phosphorylation through a membrane-associated receptor. Here the mechanism of rapid E₂-induced ERK1/2 signaling in primary cultured granule cells was investigated in more detail. The results of these studies show that E₂ and ICI182,780, a steroidal antagonist of estrogen receptor transactivation, rapidly increased ERK signaling with a time course similar to the transient activation induced by epidermal growth factor (EGF). However, EGF receptor (EGFR) autophosphorylation was not increased by E₂, and blockade of EGFR tyrosine kinase activity did not abrogate the rapid actions of E₂. The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E₂ and by blockade of E₂-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity. Inhibition of Gi signaling or protein kinase A (PKA) activity blocked the ability of ICI182,780 to rapidly stimulate ERK signaling. Under those conditions, E₂ treatment induced a rapid and transient suppression of basal ERK1/2 phosphorylation. Protein phosphatase 2A (PP2A) activity was rapidly increased by E₂ but not by E₂ covalently linked to BSA. Rapid E₂-induced increases in PP2A activity were insensitive to pertussis toxin. The presented evidence indicates that the rapid effects of estrogens on ERK signaling in cerebellar granule cells are induced through a novel G protein-coupled receptor mechanism that requires PKA and Src-kinase activity to link E₂ to the ERK/MAPK signaling module. Along with stimulating ERK signaling, E₂ rapidly activates PP2A via an independent signaling mechanism that may serve as a cell-specific regulator of signal duration.

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