Molecular pathways associated with methylmercury-induced Nrf2 modulation

Takamitsu Unoki, Masahiro Akiyama, Yoshito Kumagai, Filipe Marques Gonçalves, Marcelo Farina, João Batista Teixeira Da Rocha, Michael Aschner

Research output: Contribution to journalReview article

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number373
JournalFrontiers in Genetics
Volume9
Issue numberSEP
DOIs
StatePublished - Sep 12 2018

Fingerprint

Xenobiotics
Up-Regulation
Glycogen Synthase Kinase 3
Autophagy
Neurotoxins
Signal Transduction
Antioxidants
Metals
Phosphorylation
Brain
Enzymes
Genes
Proteins
Kelch-Like ECH-Associated Protein 1

Keywords

  • Central nervous system
  • Gene expression
  • Methylmercury
  • Nrf2
  • Toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Unoki, T., Akiyama, M., Kumagai, Y., Gonçalves, F. M., Farina, M., Da Rocha, J. B. T., & Aschner, M. (2018). Molecular pathways associated with methylmercury-induced Nrf2 modulation. Frontiers in Genetics, 9(SEP), [373]. https://doi.org/10.3389/fgene.2018.00373

Molecular pathways associated with methylmercury-induced Nrf2 modulation. / Unoki, Takamitsu; Akiyama, Masahiro; Kumagai, Yoshito; Gonçalves, Filipe Marques; Farina, Marcelo; Da Rocha, João Batista Teixeira; Aschner, Michael.

In: Frontiers in Genetics, Vol. 9, No. SEP, 373, 12.09.2018.

Research output: Contribution to journalReview article

Unoki, T, Akiyama, M, Kumagai, Y, Gonçalves, FM, Farina, M, Da Rocha, JBT & Aschner, M 2018, 'Molecular pathways associated with methylmercury-induced Nrf2 modulation', Frontiers in Genetics, vol. 9, no. SEP, 373. https://doi.org/10.3389/fgene.2018.00373
Unoki T, Akiyama M, Kumagai Y, Gonçalves FM, Farina M, Da Rocha JBT et al. Molecular pathways associated with methylmercury-induced Nrf2 modulation. Frontiers in Genetics. 2018 Sep 12;9(SEP). 373. https://doi.org/10.3389/fgene.2018.00373
Unoki, Takamitsu ; Akiyama, Masahiro ; Kumagai, Yoshito ; Gonçalves, Filipe Marques ; Farina, Marcelo ; Da Rocha, João Batista Teixeira ; Aschner, Michael. / Molecular pathways associated with methylmercury-induced Nrf2 modulation. In: Frontiers in Genetics. 2018 ; Vol. 9, No. SEP.
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