Low-dose methylmercury-induced oxidative stress, cytotoxicity, and tau-hyperphosphorylation in human neuroblastoma (SH-SY5Y) cells.
Acute neurotoxic effects of high-dose methylmercury (MeHg) in humans have been well documented in the scientific literature. However, low-dose effects are less well described. This study was designed to evaluate the effects of low-dose MeHg (<100 nM) on human brain cells in a tissue culture model. Neuroblastoma (NB) cells (SH-SY5Y) were used in the cell culture model to study low-dose effects of MeHg on cell growth, cell survival, reactive oxygen species (ROS), and the phosphorylation of tau protein, as a measure of potential markers of cellular events associated with tauopathies. When cells were incubated in culture with MeHg (50 and 100 nM), there were significant decreases in cell viability as well as significant increase in ROS generation as determined by fluorescent dye analysis (H(2)DCFDA). Furthermore, a concomitant decrease in glutathione levels to 25% of control was observed at both 50 and 100 nM MeHg. In addition, the level of phosphorylated tau was significantly increased after treatment at both 50 and 100 nM MeHg, compared with controls. Pretreatment of NB cells with the antioxidant, N-acetylcysteine (1.25 mM) and the calpain inhibitor, MDL-28170 (10 μM), significantly attenuated the effects of MeHg (50 and 100 nM) on cell viability as well as on tau phosphorylation. These results indicate that low-dose MeHg toxicity may be related to an induction of tau phosphorylation through an oxidative stress-dependent mechanism and that blockade of this pathway may attenuate the toxic effects of MeHg.
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Daniel
D
Petroni
Jeffrey
J
Tsai
Krishna
K
Agrawal
Debasis
D
Mondal
William
W
George
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry*
D000975:Antioxidants; D004151:Dipeptides; D008767:Methylmercury Compounds; D017382:Reactive Oxygen Species; D016875:tau Proteins; D019328:Buthionine Sulfoximine; D005978:Glutathione; C004925:methylmercuric chloride; C058076:calpain inhibitor III; D000111:Acetylcysteine