Molecular Pathways Associated With Methylmercury-Induced Nrf2 Modulation

Frontiers in Genetics

Takamitsu Unoki¹  Marcelo Farina²  João Batista Teixeira da Rocha³  Filipe Marques Gonçalves⁴  Michael Aschner⁴  Masahiro Akiyama⁵  Yoshito Kumagai⁵ 

[1] Department of Basic Medical Sciences, National Institute for Minamata Diseasexy3Minamata, Japan;Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil;Department of Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil;Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States;Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;

关键词: methylmercury;    toxicity;    Nrf2;    gene expression;    central nervous system;   

DOI  :  10.3389/fgene.2018.00373

来源: DOAJ

【 摘 要 】

Methylmercury (MeHg) is a potent neurotoxin that affects particularly the developing brain. Since MeHg is a potent electrophilic agent, a wide range of intracellular effects occur in response to its exposure. Yet, the molecular mechanisms associated with MeHg-induced cell toxicity have yet to be fully understood. Activation of cell defense mechanisms in response to metal exposure, including the up-regulation of Nrf2- (nuclear factor erythroid 2-related factor 2)-related genes has been previously shown. Nrf2 is a key regulator of cellular defenses against oxidative, electrophilic and environmental stress, regulating the expression of antioxidant proteins, phase-II xenobiotic detoxifying enzymes as well phase-III xenobiotic transporters. Analogous to other electrophiles, MeHg activates Nrf2 through modification of its repressor Keap1 (Kelch-like ECH-associated protein 1). However, recent findings have also revealed that Keap1-independent signal pathways might contribute to MeHg-induced Nrf2 activation and cytoprotective responses against MeHg exposure. These include, Akt phosphorylation (Akt/GSK-3β/Fyn-mediated Nrf2 activation pathway), activation of the PTEN/Akt/CREB pathway and MAPK-induced autophagy and p62 expression. In this review, we summarize the state-of-the-art knowledge regarding Nrf2 up-regulation in response to MeHg exposure, highlighting the modulation of signaling pathways related to Nrf2 activation. The study of these mechanisms is important in evaluating MeHg toxicity in humans, and can contribute to the identification of the molecular mechanisms associated with MeHg exposure.

【 授权许可】

Unknown