Endoplasmic reticulum stress manipulates autophagic response that antagonizes polybrominated diphenyl ethers quinone induced cytotoxicity in microglial BV2 cells

Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants. Previously, we reported that their quinone-type metabolite (PBDEQ) induced selective autophagy, but its biological consequences remain obscure. Here, we illustrated the possible link of PBDEQ-induced autophagy with endoplasmic reticulum (ER) stress and cytotoxicity in microglial BV2 cells. We found PBDEQ increased the formation of autophagosomes, promoted autophagic degradation, suggesting an improved autophagy flux in BV2 cells. Interestingly, both pharmacologic autophagy inhibitors and autophagy-related 5 gene small interfering RNA (ATG5 siRNA) aggravated the cytotoxicity of PBDEQ, suggesting the antagonizing role of autophagy. PBDEQ induced ER stress and activated protein kinase R-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) axis of classic unfolded protein response (UPR) pathway, whilst ER stress inhibitor blocked PBDEQ-induced autophagy. Moreover, N-acetyl-L-cysteine (NAC) alleviated PBDEQ-induced activation of ER stress and autophagy, suggesting reactive oxygen species (ROS) were involved in regulating PBDEQ-induced ER stress and autophagy. Taken together, our results demonstrate a new mechanism of PBDEQ-associated toxicity.