title: The role of the IRE1 pathway in PBDE-47-induced toxicity in human neuroblastoma SH-SY5Y cells in vitro.
abstract: Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants. As one of the dominant congeners, 2,2', 4,4'-tetrabromodiphenyl ether (PBDE-47) has been shown to be neurotoxic to neuronal cells although the mechanisms remain unclear. To test whether PBDE-47's toxicity was related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), human neuroblastoma cells (SH-SY5Y cells) were treated with different concentrations of PBDE-47. Reactive oxygen species (ROS), apoptosis and the expressions of the inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. PBDE-47 exposure increased ROS production and activated the UPR by increasing the expressions of glucose-regulated protein 78 (GRP78), IRE1, X-box-binding protein-1 (XBP1), phosphorylation of c-jun N-terminal kinase (JNK) and GADD153/C/EBP homologous protein (CHOP) genes in SH-SY5Y cells. The apoptotic rate increased with the remarkable up-regulation of the Bax/Bcl-2 ratio after IRE1 knockdown, demonstrating the anti-apoptotic role of IRE1. Furthermore, the expressions of CHOP, XBP1 and JNK were down-regulated indicating that IRE1 may activate these key molecules related to apoptosis. PBDE-47 exposure can increase ROS production and activate the IRE1 pathway of the UPR in SH-SY5Y cells contributing to its toxicity. The IRE1 pathway may have both protective and proapoptotic effects on SH-SY5Y cells.
authors.affiliation: School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, PR China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jiang
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Tao
authors.initials: T
authors.lastname: Xia
authors.forename: Yihu
authors.initials: Y
authors.lastname: Chen
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: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wang
mesh_terms: D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006690:Bisbenzimidazole; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000502:physiology*; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006801:Humans; D007202:Indicators and Reagents; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D017304:Annexin A5; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D055768:Halogenated Diphenyl Ethers; D007202:Indicators and Reagents; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C086401:pentabromodiphenyl ether; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D006690:Bisbenzimidazole