Methylmercury (MeHg) is a well-known neurotoxicant that causes severe intoxication in humans. In Japan, it is referred to as Minamata disease, which involves two characteristic clinical forms: fetal type and adult type depending on the exposed age. In addition to MeHg burden level, individual susceptibility to MeHg plays a role in the manifestation of MeHg toxicity. Research progress has pointed out the importance of oxidative stress in the pathogenesis of MeHg toxicity. MeHg has a high affinity for selenohydryl groups, sulfhydryl groups, and selenides. It has been clarified that such affinity characteristics cause the impairment of antioxidant enzymes and proteins, resulting in the disruption of antioxidant systems. Furthermore, MeHg-induced intracellular selenium deficiency due to the greater affinity of MeHg for selenohydryl groups and selenides leads to failure in the recoding of a UGA codon for selenocysteine and results in the degradation of antioxidant selenoenzyme mRNA by nonsense-mediated mRNA decay. The defect of antioxidant selenoenzyme replenishment exacerbates MeHg-mediated oxidative stress. On the other hand, it has also been revealed that MeHg can directly activate the antioxidant Keap1/Nrf2 signaling pathway. This review summarizes the incidence of MeHg-mediated oxidative stress from the viewpoint of the individual intracellular redox system interactions and the MeHg-mediated aforementioned intracellular events. In addition, the mechanisms of cellular stress pathways and neuronal cell death triggered by MeHg-mediated oxidative stress and direct interactions of MeHg with reactive residues of proteins are mentioned.
Keywords: Keap1/Nrf2 pathway; binding affinity; methylmercury; nonsense-mediated mRNA decay; oxidative stress; posttranscriptional defect; redox signaling; selenoenzyme; thiol antioxidant capacity.