Methylmercury toxicity and Nrf2-dependent detoxification in astrocytes.

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.