Role of Nrf2 in the antioxidation and oxidative stress induced developmental toxicity of honokiol in zebrafish

Honokiol, the main bioactive component of Magnolia officinalis, has a variety of pharmacological actions. However, its toxicity has rarely been reported. According to previous studies performed in our laboratory, honokiol microemulsion has embryo developmental toxicity. For further exploration, Zebrafish embryos were exposed to different doses of honokiol microemulsion to record the rates of mortality, malformation, and hatching. We found that high doses of honokiol microemulsion (0.6 and 0.9 mu g/ml) increased mortality, inhibited hatching, caused malformation and reduced swimming activities. The low-dose group (0.15 and 0.30 mu g/ml) had decreased production of reactive oxygen species (ROS), but the high-dose group had inhibited super-oxide dismutase (SOD) enzyme activity and increased ROS content. The mRNA expression of soda, sod2, catalase (cat), and heme oxygenase 1 (ho1) was up-regulated at low doses but down-regulated at high doses. The nuclear factor E2-related factor 2 (Nrf2) mRNA expression increased at low doses but decreased at high doses. After knocking down Nrf2 in zebrafish embryos, the rates of mortality and malformation were markedly increased and the hatching rate was significantly decreased. These results suggest that honokiol has antioxidative effects at low doses but causes embryo-developmental toxicity at high doses, and the Nrf2 gene may play a pivotal role in regulating these processes.