title: Low in situ expression of antioxidative enzymes in rat cerebellar granular cells susceptible to methylmercury.
abstract: Methylmercury (MeHg), an environmental neurotoxicant, induces site-specific toxicity in the brain. Although oxidative stress has been demonstrated with MeHg toxicity, the site-specific toxicity is not completely understood. Among the cerebellar neurons, cerebellar granule cells (CGCs) appear vulnerable to MeHg, whereas Purkinje cells and molecular layer neurons are resistant. Here, we use a MeHg-intoxicated rat model to investigate these cerebellar neurons for the different causes of susceptibility to MeHg. Rats were exposed to 20 ppm MeHg for 4 weeks and subsequently exhibited neuropathological changes in the cerebellum that were similar to those observed in humans. We first isolated the three cerebellar neuron types using a microdissection system and then performed real-time PCR analyses for antioxidative enzymes. We observed that expression of manganese-superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1), and thioredoxin reductase 1 (TRxR1) was significantly higher in Purkinje cells and molecular layer neurons than in CGCs. Finally, we performed immunohistochemical analyses on the cerebellum. Immunohistochemistry showed increased expression of Mn-SOD, GPx1, and TRxR1 in Purkinje cells and molecular layer neurons, which was coincident with the mRNA expression patterns. Considering Mn-SOD, GPx1, and TRxR1 are critical for protecting cells against MeHg intoxication, the results indicate that low expression of these antioxidative enzymes increases CGCs vulnerability to MeHg toxicity.
authors.affiliation: Department of Basic Medical Sciences, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto, 867-0008, Japan, fujimura@nimd.go.jp.
authors.forename: M
authors.initials: M
authors.lastname: Fujimura
authors.forename: F
authors.initials: F
authors.lastname: Usuki
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D042282:Microdissection / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011689:Purkinje Cells / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D004798:Enzymes; D008767:Methylmercury Compounds; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D054481:Thioredoxin Reductase 1; C516126:Txnrd1 protein, rat; D000094765:Glutathione Peroxidase GPX1; C000722069:Gpx1 protein, rat