Troxerutin inhibits 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-induced hepatocyte apoptosis by restoring proteasome function

• BDE-47 promotes hepatocyte apoptosis by triggering proteasome dysfunction.
• Troxerutin inhibits BDE-47-induced hepatocyte apoptosis via its antioxidant activity.
• Troxerutin restores hepatic proteasome function and consequently inhibits ER stress.
• Troxerutin blocks ER stress-mediated apoptotic pathway in BDE-47-treated mouse livers.
• Troxerutin may be used in prevention and therapy of BDE-47-induced hepatotoxicity.

Proteasome dysfunction has been associated with the pathogeneses of a variety of diseases and with the neurotoxicities of environmental chemicals; however, whether proteasome dysfunction plays a role in the cellular toxicity of polybrominated diphenyl ethers (PBDEs) has not been investigated to date. Emerging evidence suggests that antioxidants exhibit evident beneficial effects on the cellular toxicity associated with PBDEs. In the present study, we investigated whether troxerutin attenuates BDE-47-induced hepatocyte apoptosis by restoring proteasome function and explored the mechanisms underlying this effect. Our results revealed that proteasome dysfunction was involved in the BDE-47-induced hepatocyte apoptosis in the mouse liver. Furthermore, our results revealed that troxerutin effectively inhibited hepatocyte apoptosis by restoring oxidative stress-mediated proteasome dysfunction in BDE-47-treated mice. Consequently, troxerutin markedly suppressed endoplasmic reticulum (ER) stress in the livers of the BDE-47-treated mice. The inhibitory effects of troxerutin on ER stress and apoptotic pathways were markedly blunted by treatment with epoxomicin (a selective inhibitor of proteasome). Ultimately, troxerutin dramatically blocked TRAF2-ASK1-JNK signaling and CHOP-mediated apoptosis signaling in the BDE-47-treated mouse livers. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be a candidate for the prevention of and therapy for BDE-47-induced hepatotoxicity.