Effect of 2, 2', 4, 4'-Tetrabromodiphenyl Ether (BDE-47) and Its Metabolites on Cell Viability, Oxidative Stress, and Apoptosis of HepG2.

2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47), an extensively used brominated flame retardant (BFR), is frequently detected in biotic environments. To date, studies have reported that BDE-47 induces hepatotoxicity, reproductive toxicity, and neurotoxicity in vitro. However, little is known regarding BDE-47 metabolites-mediated cell toxicity in relevant human cell models. The cytotoxic effects of BDE-47 and its eight metabolites on hepatoblastoma cell line-HepG2 cells were investigated in this study. We found that BDE-47 and all its metabolites inhibited cell viability in both a dose- and time-dependent manner. For BDE-47 and its debromination products (BDE-28 and BDE-7), they had less severe effects on cell viability when the cells were pretreated with lower dose of the same compound, however, no significant difference was observed in control, suggesting that low concentrations have an adaptation effect on HepG2 cells. BDE-47 and its metabolites also induce changes in ROS generation, SOD and GSH activity, cell cycle regulation, DNA damage and cell apoptosis, indicating that the toxicity mechanisms of BDE-47 and its degradation products are mediated by oxidative stress, DNA damage and cell cycle dysregulation. Moreover, brominated phenol products (2,4-DBP and 4-BP) posed the highest toxic effects on HepG2, followed by hydroxylated products (6-OH-BDE-47, 5-OH-BDE-47, 2-OH-BDE-28, and 4-OH-BDE-17), and BDE-47 and its debromination products were comparatively less toxic to HepG2 cells. Taken together, these results demonstrate the hepatotoxic potential of BDE-47 and its metabolites.