title: The brominated flame retardant BDE-47 causes oxidative stress and apoptotic cell death in vitro and in vivo in mice.
abstract: Polybrominated diphenyl ethers (PBDEs), used for decades as flame retardants, have become widespread environmental contaminants. Exposure is believed to occur primarily through diet and dust, and infants and toddlers have the highest body burden, raising concern for potential developmental neurotoxicity. The exact mechanisms of PBDE neurotoxicity have not been elucidated, but two relevant modes of action relate to impairment of thyroid hormone homeostasis and to direct effects on brain cells causing alterations in signal transduction, oxidative stress and apoptotic cell death. The present study shows that BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) induces oxidative stress and ensuing apoptotic cell death in mouse cerebellar granule neurons in vitro. Similarly, in vivo administration of BDE-47, according to an exposure protocol shown to induce behavioral and biochemical alterations (10mg/kg, per os on post-natal day 10), induces oxidative stress and apoptosis, without altering serum levels of thyroid hormones. The effects of BDE-47 both in vitro and in vivo were more pronounced in a mouse model lacking the modifier subunit of glutamate cysteine ligase (GCLM) which results in reduced anti-oxidant capability due to low levels of GSH. Concentrations of BDE-47 in brain were in the mid-nanomolar range. These findings indicate that effects observed with BDE-47 in vitro are also present after in vivo administration, suggesting that in addition to potential endocrine effects, which were not seen here, direct interactions with brain cells should be considered as a potential mechanism of BDE-47 neurotoxicity.
authors: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Department Neuroscience, University of Parma, Parma, Italy. Electronic address: lgcosta@u.washington.edu.
authors: Lucio G
authors: LG
authors: Costa
authors: Department Neuroscience, University of Parma, Parma, Italy.
authors: Claudia
authors: C
authors: Pellacani
authors: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors: Khoi
authors: K
authors: Dao
authors: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors: Terrance J
authors: TJ
authors: Kavanagh
authors: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors: Pamela J
authors: PJ
authors: Roque
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005411:Flame Retardants / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000235:genetics; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D018570:Risk Assessment; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D015415:Biomarkers; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D013963:Thyroid Hormones; C511295:2,2',4,4'-tetrabromodiphenyl ether; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase
keywords: Apoptosis; BDE-47; Glutathione; Oxidative stress; Thyroid hormone