title: Some commonly used brominated flame retardants cause Ca2+-ATPase inhibition, beta-amyloid peptide release and apoptosis in SH-SY5Y neuronal cells.
abstract: Brominated flame retardants (BFRs) are chemicals commonly used to reduce the flammability of consumer products and are considered pollutants since they have become widely dispersed throughout the environment and have also been shown to bio-accumulate within animals and man. This study investigated the cytotoxicity of some of the most commonly used groups of BFRs on SH-SY5Y human neuroblastoma cells. The results showed that of the BFRs tested, hexabromocyclododecane (HBCD), tetrabromobisphenol-A (TBBPA) and decabromodiphenyl ether (DBPE), all are cytotoxic at low micromolar concentrations (LC(50) being 2.7 ± 0.7 µM, 15 ± 4 µM and 28 ± 7 µM, respectively). They induced cell death, at least in part, by apoptosis through activation of caspases. They also increased intracellular [Ca(2+)] levels and reactive-oxygen-species within these neuronal cells. Furthermore, these BFRs also caused rapid depolarization of the mitochondria and cytochrome c release in these neuronal cells. Elevated intracellular [Ca(2+)] levels appear to occur through a mechanism involving microsomal Ca(2+)-ATPase inhibition and this maybe responsible for Ca(2+)-induced mitochondrial dysfunction. In addition, µM levels of these BFRs caused β-amyloid peptide (Aβ-42) processing and release from these cells with a few hours of exposure. These results therefore shows that these pollutants are both neurotoxic and amyloidogenic in-vitro.
authors.affiliation: School of Biosciences, University Of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Al-Mousa
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005411:Flame Retardants / Q000633:toxicity*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D045304:Cytochromes c; D020169:Caspases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium