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ToxSci Advance Access published online on August 8, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl073
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 20, 2006
Accepted July 25, 2006

Neurotoxicology

Mercury Abolishes Neurotrophic Factor-Stimulated Jak-STAT Signaling in Nerve Cells by Oxidative Stress

Richard K. Monroe 1 and Stanley W. Halvorsen 2 *

1 Program in Neurosciences, 102 Farber Hall, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214-3000
2 Program in Neurosciences, 102 Farber Hall, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214-3000; Department of Pharmacology and Toxicology, 102 Farber Hall, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214-3000

* To whom correspondence should be addressed.
Stanley W. Halvorsen, E-mail: stanh{at}buffalo.edu


  Abstract

Mercury is a potent neurotoxin that can delay neurological development in neonates, and has been proposed to be an environmental risk factor for several neurodegenerative conditions. The mechanisms by which environmental factors may influence the propagation of neurodegenerative diseases are not yet well delineated. However, it is known that neurons require trophic factor support for maintenance and survival following traumatic physical and toxic insults. We found that divalent mercury (HgCl2) inhibited ciliary neurotrophic factor (CNTF) and interferon-{gamma} receptor-mediated Jak tyrosine kinase-STAT (signal transducers and activators of transcription) pathway activation in SK-N-BE(2)C neuroblastoma cell cultures, but did not inhibit the fibroblast growth factor receptor tyrosine kinase. Results of dichlorofluorescein experiments showed increased levels of oxidative stress in HgCl2-treated cells that was similar in magnitude to that caused by treatment with H2O2. The antioxidant agents glutathione, N-acetylcysteine and sodium ascorbate each protected neurons against HgCl2-induced inhibition of STAT activation. HgCl2 also inhibited Jak-STAT signaling in cultures of chick retina neurons, but did not affect signaling in non-neuronal HepG2 cells and chick skeletal myotubes. The specific inhibition of growth factor mediated Jak-STAT signaling pathways in neurons by HgCl2-induced oxidative stress offers a new mechanism by which mercury may produce neurotoxic symptoms in the developing nervous system, promote neurodegeneration in mature neurons, and inhibit recovery following neurotrauma.

Keywords: Ciliary neurotrophic factor; gp130; tyrosine kinase; cytokine; interferon-{gamma}; transition metals; signal transduction; neurotoxicity.
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