title: The sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) is the likely molecular target for the acute toxicity of the brominated flame retardant hexabromocyclododecane (HBCD).
abstract: Hexabromocyclododecane (HBCD) is a widely utilised brominated flame retardant (BFR). It has been shown to bio-accumulate within organisms, including man, and possibly cause neurological disorders. The acute neurotoxicity of HBCD, and six other unrelated BFRs, were assessed in SH-SY5Y human neuroblastoma cells by 24h viability assays and HBCD proved to be the most lethal (LC50, 3μM). In addition, the effects of these BFRs were also assessed for their potency at inhibiting the sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA) derived from the SH-SY5Y cells and again HBCD was the most potent (IC50, 2.7μM). The data for the other BFRs tested showed a direct correlation (coefficient 0.94) between the potencies of inducing cell death and inhibiting the Ca(2+) ATPase, indicating that SERCA is likely to be the molecular target for acute toxicity. Mechanistic studies of HBCD on the Ca(2+) ATPase suggest that it affects ATP binding, phosphorylation as well as the E2 to E1 transition step.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Al-Mousa
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: F.Michelangeli@Bham.ac.uk.
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity*; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D008274:Magnesium / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023382:Toxicity Tests, Acute
chemical_list: D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; C089796:hexabromocyclododecane; D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016650:Fluorescein-5-isothiocyanate; D008274:Magnesium; D002118:Calcium
keywords: BFRs; Brominated flame retardant; HBCD; Hexabromocyclododecane; SERCA; SERCA Ca(2+) pumps; TBBPA; brominated flame retardants; hexabromocyclododecane; sarcoplasmic–endoplasmic reticulum Ca(2+) ATPase; tetrabromobisphenol-A