Abstract
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.
Highlights
Methylmercury (MeHg) is a well-established neurotoxicant that affects various cellular functions depending on the cellular context and developmental phase
We previously demonstrated that cerebellar granule cells susceptible to MeHg have lower in situ expression of Manganese-superoxide dismutase (Mn-SOD), GPx1, and TRxR1 mRNAs than cerebellar molecular layers and Purkinje cells, which are known to be resistant to MeHg [49]
We demonstrated early expression of the oxidative stress marker thymidine glycerol followed by activation of p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK, and an increase in cAMP response element binding protein (CREB) pathways
Summary
Methylmercury (MeHg) is a well-established neurotoxicant that affects various cellular functions depending on the cellular context and developmental phase. The high affinity of MeHg for selenohydryl groups, sulfhydryl groups, and selenides results in the impairment of antioxidant enzymes and proteins as well as the subsequent disruption of antioxidant systems, which leads to MeHg-mediated oxidative stress. The high affinity of MeHg for selenohydryl groups and selenides causes intracellular relative active selenium (Se) deficiency Such MeHg-induced Se deficiency 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 (NMD). NMD has been considered an mRNA quality surveillance mechanism to protect an organism against deleterious dominant-negative or gain-of-function effects of truncated proteins that arise from PTCs. The incidence of MeHg-mediated oxidative stress should depend on the individual capacities of the intracellular redox systems to respond to the results of the interactions among the aforementioned MeHg-induced events. Recent works clarified the molecular mechanism of MeHg-induced apoptosis and cortical neuronal cell death caused by MeHg-mediated oxidative stress
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