Subacute exposure of 2, 2′, 4, 4′-tetrabromodiphenyl ether induced liver injury by inhibiting mitochondrial autophagy and increasing NLRP3 inflammasome in mice

Abstract

2′,4,4′-tetrabrominated diphenyl ethers (BDE-47) is one of the most common brominated flame retardants found in environment and has been demonstrated to be associated with a variety of adverse human health effects. It has been proven to generate liver toxicity, but little is known about the potential mechanism following BDE-47 exposure. Here, hepatotoxicity of BDE-47 in mice was investigated by gavage exposure to BDE-47 (12.5–100mg/kg/day) for 4 weeks. The results showed the increasing of ALT and AST in serum and histopathological change of liver in BDE-47 exposure mice. In addition, we observed that the mitochondrial membrane potential (MMP) decreased and ROS increased with the increase of BDE-47 dose. BDE-47 also up-regulated NLRP3 protein levels, and proteins expression of caspase-1, IL-1β, IL-18 and TNF-α inflammatory factors. Furthermore, mitophagy was blocked with Parkin and PINK1 protein expression decrease and P62 increase in liver of BDE-47 exposure mice. However, activation of mitophagy with autophagy activator rapamycin (RAPA) alleviated liver injury induced by BDE-47 in mice via increasing the protein expression of PINK1 and Parkin, and decreasing NLRP3 and inflammatory factors. These results suggest NLRP3 inflammasome activation-mediated mitochondrial and liver damage in BDE-47-exposed mice is due to mitophagy downregulation, and activating mitophagy can alleviate BDE-47-induced inflammatory damage by regulating NLRP3 inflammasome.