BDE-47 induced PC-12 cell differentiation via TrkA downstream pathways and caused the loss of hippocampal neurons in BALB/c mice

As the most abundant congener of polybrominated diphenyl ethers (PBDEs) detected in environment and human biotic samples, 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) has been found to accumulate in brain and induce neurotoxicity, however, the detailed mechanism has not been clearly elucidated. To investigate the neurotoxicity of BDE-47, undifferentiated PC-12 cells were exposed to different doses of BDE-47, and BDE-47 dissolved in corn oil was orally administered to mice for 8 consecutive weeks. Our data showed that BDE-47 obviously changed cell morphology, altered cell viability, promoted cell Apoptosis, and induced Reactive Oxygen Species (ROS) production. BDE-47 promoted the differentiation of PC-12 cells by enhancing the expression of TrkA receptor and the phosphorylation levels of ERK and Akt. Moreover, BDE-47-induced differentiation of PC-12 cells was suppressed by inhibitors of corresponding pathways (MAPK/ERK and PI3K/Akt). H&E staining of brain showed neurons in DG and CA1 areas of hippocampus decreased after BDE-47 exposure. Transcriptome Sequencing of brain tissue suggested that multiple signaling pathways related to neuron death and nerve function were significantly regulated. In conclusion, these results provided new evidence for revealing the neurotoxicity of BDE-47, and offered important experimental basis for environmental controlling and post-exposure health risk assessment of BDE-47.