title: Involvement of the mitochondrial p53 pathway in PBDE-47-induced SH-SY5Y cells apoptosis and its underlying activation mechanism.
abstract: 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47)-elicited neurotoxicity is associated with neural apoptosis; however the underlying mechanisms remain unclear. To investigate whether the mitochondrial p53 pathway is involved in neuronal apoptosis induced by PBDE-47 and to correlate DNA hypomethylation with p53 activation, human neuroblastoma (SH-SY5Y) cells were treated with different concentrations of PBDE-47 (1, 5, 10 μmol/L) for 24h in vitro. The apoptosis and ultrastructural alterations in cells, levels of p53, Bcl-2, Bax, cytochrome c (Cyt c), caspase-3 and methylation status of p53 promoter were determined. Hoechst 33258 staining and transmission electron microscopy analysis showed that PBDE-47 induced SH-SY5Y cells apoptosis characterized by the typical apoptotic morphological changes. In addition, PBDE-47 activated the p53-dependent mitochondrial apoptotic pathway as evidenced by up-regulation of p53 and Bax, down-regulation of Bcl-2 and Bcl-2/Bax ration, enhancement of Cyt c release from mitochondria into the cytosol, activation of caspase-3 as well as ultrastructural abnormalities of mitochondria. However, no obvious decrease in p53 promoter methylation levels was observed in any of the treatment groups by bisulfite genomic sequencing. Collectively, these results suggest that the mitochondrial p53 pathway is involved in PBDE-47-induced SH-SY5Y cells apoptosis, nevertheless p53 promoter hypomethylation may not be implicated in this process.
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, PR China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhao
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lei
authors.forename: Tao
authors.initials: T
authors.lastname: Xia
authors.forename: Jianbin
authors.initials: J
authors.lastname: Chen
authors.forename: Zhenglun
authors.initials: Z
authors.lastname: Wang
authors.forename: Rulin
authors.initials: R
authors.lastname: Ma
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000648:ultrastructure; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006801:Humans; D008745:Methylation; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D055768:Halogenated Diphenyl Ethers; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C511295:2,2',4,4'-tetrabromodiphenyl ether; D045304:Cytochromes c; D053148:Caspase 3
keywords: Apoptosis; Methylation; Neurotoxicity; PBDE-47; p53 Pathway