title: Role of glutamate receptors in tetrabrominated diphenyl ether (BDE-47) neurotoxicity in mouse cerebellar granule neurons.
abstract: The polybrominated diphenyl ether (PBDE) flame retardants are developmental neurotoxicants, as evidenced by numerous in vitro, animal and human studies. PBDEs can alter the homeostasis of thyroid hormone and directly interact with brain cells. Induction of oxidative stress, leading to DNA damage and apoptotic cell death is a prominent mechanism of PBDE neurotoxicity, though other mechanisms have also been suggested. In the present study we investigated the potential role played by glutamate receptors in the in vitro neurotoxicity of the tetrabromodiphenyl ether BDE-47, one of the most abundant PBDE congeners. Toxicity of BDE-47 in mouse cerebellar neurons was diminished by antagonists of glutamate ionotropic receptors, but not by antagonists of glutamate metabotropic receptors. Antagonists of NMDA and AMPA/Kainate receptors also inhibited BDE-47-induced oxidative stress and increases in intracellular calcium. The calcium chelator BAPTA-AM also inhibited BDE-47 cytotoxicity and oxidative stress. BDE-47 caused a rapid increase of extracellular glutamate levels, which was not antagonized by any of the compounds tested. The results suggest that BDE-47, by still unknown mechanisms, increases extracellular glutamate which in turn activates ionotropic glutamate receptors leading to increased calcium levels, oxidative stress, and ultimately cell death.
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Dept. of Neuroscience, University of Parma, Parma, Italy. Electronic address: lgcosta@u.washington.edu.
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Dept. of Neuroscience, University of Parma, Parma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tagliaferri
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Roqué
authors.affiliation: Dept. of Neuroscience, University of Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pellacani
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D002614:Chelating Agents / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005411:Flame Retardants / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects*; D058468:Receptors, Ionotropic Glutamate / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
chemical_list: D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D058468:Receptors, Ionotropic Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C511295:2,2',4,4'-tetrabromodiphenyl ether; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D002118:Calcium
keywords: AMPA/Kainate; BDE-47; Developmental neurotoxicity; Flame retardants; Glutamate receptors; NMDA