Nrf2 and STAT3 Pathways in Protecting Against Methylmercury-Induced Oxidative Stress in Hypothalamic Neuronal GT1-7 Cells

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Abstract
Oxidative stress plays a critical role in the methylmercury (MeHg) neurotoxicity, as MeHg induces reactive oxygen species (ROS) generation and impairs antioxidant defense systems. However, the precise molecular mechanisms underlying MeHg-induced neurotoxicity remain elusive. The nuclear factor erythroid 2-related factor 2 (Nrf2) activates antioxidant defense genes in response to acute MeHg exposure. Similarly, the signal transducer and activator of transcription 3 (STAT3), a transcription factor involved in cell growth and anti-apoptotic genes, also contributes to maintaining redox homeostasis. Here, we sought to investigate the roles of Nrf2 and STAT3 in mouse hypothalamic neuronal GT1-7 cells exposed to MeHg. We inhibited STAT3 either pharmacologically with AG490 (a JAK2 inhibitor) or C188-9 (a small-molecule STAT3 SH2 domain inhibitor) or genetically using a lentivirus carrying STAT3 shRNA (vs. scramble control), in GT1-7 cells exposed to 5 µM MeHg. To further dissect the role of Nrf2, the pathway was pharmacologically inhibited using brusatol or activated with sulforaphane (SFN) in GT1-7 cells co-exposed to 5 µM MeHg. Changes in cell viability, reactive species production, and protein and gene expression were analyzed. Our findings reveal that deficits of either the Nrf2 or STAT3 pathways exacerbated MeHg-induced toxicity. Moreover, in MeHg-exposed cells, Nrf2 ablation led to increased STAT3 activity, suggesting a reciprocal and potentially compensatory responses between these two pathways in protecting against MeHg-induced oxidative stress. Our novel findings provide crucial understanding of the molecular mechanisms underlying MeHg neurotoxicity and offer insights into potential therapeutic strategies for mitigating acute MeHg-induced neurotoxicity. Graphical Abstract
Funding Information
  • Ministry of Science and Higher Education of the Russian Federation (075-15-2024-550)
  • National Institute of Environmental Health Sciences (R01ES007331)
  • National Institute of Environmental Health Sciences (R01ES007331)

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