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

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.

► PBDE-47 may have toxicity through inducing ER stress mediated by ROS production and UPR in SH-SY5Y cells. ► Exposed to PBDE-47, IRE1 has bi-functional roles of anti- and pro-apoptosis by mediating the expressions of Bcl-2, Bax, XBP1, JNK and CHOP genes in SH-SY5Y cells. ► IRE1 may be a key mediator of the cytotoxic effect of PBDE-47 in nerve cells.