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ToxSci Advance Access originally published online on September 23, 2008
Toxicological Sciences 2009 107(1):135-143; doi:10.1093/toxsci/kfn201
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Methylmercury Toxicity and Nrf2-dependent Detoxification in Astrocytes

Ling Wang*,{dagger}, Haiyan Jiang{ddagger}, Zhaobao Yin{ddagger}, Michael Aschner{ddagger} and Jiyang Cai*,1

* Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232 {dagger} EENT Hospital, Fudan University, Shanghai, China {ddagger} Departments of Pediatrics and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232

1 To whom correspondence should be addressed at Vanderbilt Eye Institute, Vanderbilt University Medical Center, 11425 Medical Research Building IV, 2213 Garland Avenue, Nashville, TN 37232-8808. Fax: (615)-936-6410. E-mail: jiyang.cai{at}vanderbilt.edu.

Received May 28, 2008; accepted September 16, 2008


  Abstract

Methylmercury (MeHg) is a potent neurotoxicant and preferentially induces oxidative injury in astrocytes. In neuronal tissues, nuclear factor erythroid 2–related factor 2 (Nrf2) is a key factor determining the protective antioxidant response against various environmental toxicants. Nrf2 is subjected to regulation by many other signaling pathways. The purpose of this study is to characterize its interaction with the phosphatidylinositol 3 (PI3) kinase in cultured rat neonatal primary astrocytes. The results showed that at pathologically relevant concentrations, exposure of primary astrocytes to MeHg led to Nrf2 activation and upregulation of its downstream antioxidant genes. Inhibition of the PI3 kinase resulted in decreased Nrf2 activity, decreased cellular glutathione, and increased cell death to high-dose MeHg. The functional interaction between the two signaling pathways underlined an important mechanism for astrocyte protection against MeHg toxicity. Modulation of Nrf2 by pharmacological modalities should afford a treatment to attenuate MeHg-induced neurotoxicity.

Key Words: methylmercury; astrocyte; glutathione; Nrf2; phosphatidylinositol 3 kinase.


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