title: Exposure to an environmental neurotoxicant hastens the onset of amyotrophic lateral sclerosis-like phenotype in human Cu2+/Zn2+ superoxide dismutase 1 G93A mice: glutamate-mediated excitotoxicity.
abstract: Mice expressing the human Cu(2+)/Zn(2+) superoxide dismutase 1 (hSOD1) gene mutation (hSOD1(G93A); G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca(2+)](i)) in soma of brainstem-hypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca(2+)](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes Ca(2+)-permeable AMPA receptors, further reduced [Ca(2+)](i) more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg-treated mice have a greater Ca(2+)-permeable AMPA receptor contribution. The non-Ca(2+) divalent cation chelator N,N,N',N'-tetrakis(pyridylmethyl)ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn(2+) indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn(2+) apparently contributed measurably to the MeHg-induced effect. This is the initial demonstration of accelerated onset of ALS-like phenotype in a genetically susceptible organism by exposure to low concentrations of an environmental neurotoxicant. Increased [Ca(2+)](i) induced by the G93A-MeHg interaction apparently was associated with Ca(2+)-permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca(2+)](i), leading to excitotoxic cell death.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Johnson
authors.forename: Yukun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Hajela
authors.forename: Alisha
authors.initials: A
authors.lastname: Chitrakar
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Parsell
authors.forename: William D
authors.initials: WD
authors.lastname: Atchison
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D018690:Excitatory Amino Acid Agonists; D008767:Methylmercury Compounds; D018698:Glutamic Acid; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase