Tetrabromobisphenol A and hexabromocyclododecane, brominated flame retardants, trigger endoplasmic reticulum stress and activate necroptosis signaling in PC12 cells

Tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) are brominated flame retardants commonly used in a variety of industrial and consumer products. In this study, we performed RNA sequencing analysis of PC12 cells to clarify the mechanisms by which TBBPA and HBCD induce neurotoxicity. Differential expression analysis demonstrated that 636 and 271 genes were differentially expressed after TBBPA and HBCD treatment, respectively. Gene Ontology (GO) enrichment analysis revealed that genes annotated with the GO term "endoplasmic reticulum unfolded protein response" were upregulated in both TBBPA-and HBCD-treated groups. Furthermore, protein expression of endoplasmic reticulum stress markers, such as HSPA5 and DDIT3, as well as cleaved caspase-3, an apoptosis marker, were induced by TBBPA and HBCD. We also found that the cytotoxicity induced by TBBPA and HBCD was blocked by necrostatin-1, a necroptosis inhibitor, indicating the contribution of necroptosis. Our findings provide new insight into the mechanisms of toxicity induced by these chemicals.