Polybrominated diphenyl ethers (PBDE) have been widely applied as flame retardants in plastics, polyurethane foam, paints, and synthetic fabrics. The rising PBDE level in human tissues and environment has led to concern about the health impact of exposure to PBDE. The 2,2',4,4'-tetrabromodiphenyl ether (BDE47), the dominant PBDE congener found in the environment and human tissues, has been shown to be an endocrine disruptor. It has also been reported to cause liver and neurodevelopmental toxicity. BDE47 can be metabolized to 6-OH-BDE47 and 6-MeO-BDE47. So far little has been reported on the cytotoxicity of the metabolites. In the present study, the cytotoxicity of the two metabolites was investigated by exposing human hepatoma cell line HepG2 to different doses of 6-OH-BDE47 and 6-MeO-BDE47. The cell viability, cell cycle, apoptosis, DNA damage, micronucleus levels, and oxidative stress response were studied. The results indicated that both metabolites could markedly inhibit the proliferation of HepG2 cells with 6-OH-BDE47 showing a stronger effect, and significantly increase the micronucleus level and apoptosis rate in a dose-dependant manner. Moreover, treatment with 6-OH-BDE47 (≥0.5 μM) resulted in a marked cell cycle block. The SCGE experiments revealed that both metabolites could cause DNA damage in a dose-dependant manner. Analysis of the oxidative stress response showed that 6-OH-BDE47 treatment (≥2.0 μM) significantly increased intracellular ROS levels as indicated by GSH depletion and elevation of SOD level, whereas 6-MeO-BDE47 showed a weaker effect, suggesting that oxidative stress might play a role in the cytotoxic effects. We concluded that 6-OH-BDE47 or 6-MeO-BDE47 exposure was able to induce inhibition of cell viability, increase of apoptosis rate, cell cycle block, and DNA damages, which might involve the alterated oxidative stress response due to the elevated free radicals and impaired antioxidative system.
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