The role of the IRE1 pathway in PBDE-47-induced toxicity in human neuroblastoma SH-SY5Y cells in vitro

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• 作者：Chunyang Jiang^a ; ¹ ; Shun Zhang^a ; ¹ ; Hongliang Liu^b ; Qiang Zeng^b ; Tao Xia^a ; Yihu Chen^a ; Gang Kuang^a ; Guodong Zhao^a ; Xue Wu^a ; Xiaofei Zhang^a ; Aiguo Wang^a ; ^{wangaiguo@mails.tjmu.edu.cn}
• 关键词：Apoptosis ; Endoplasmic reticulum stress ; Unfolded protein response ; IRE1 ; PBDE-47
• 刊名：Toxicology Letters
• 出版年：2012
• 期刊代码：49_03784274
• 类别：pha
• 出版时间：20 June, 2012
• 卷：211
• 期：3
• 页码：325-333
• 文件大小：1456 K

摘要

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants. As one of the dominant congeners, 2,2鈥? 4,4鈥?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.