Toxic effects of flufenoxuron on development and vascular formation during zebrafish embryogenesis

Flufenoxuron, a chitin synthesis inhibitor that is widely used in developed countries as an insecticide, is rarely degraded in the environment. In addition to that in insects, flufenoxuron-mediated non-targeted death in organisms such as lizards and bees has been reported. However, the toxic effects of this compound on vascular development during embryogenesis, as well as the underlying mechanism, have not yet been elucidated. In the present study, we assessed abnormal development and cardiovascular damage induced by flufenoxuron in zebrafish embryos. Exposed zebrafish had malformed eyes and pathological characteristics such as heart and yolk sac edema. In accordance with developmental inhibition, cell cycle regulatory genes were dysregulated in zebrafish embryos upon exposure to flufenoxuron. We also discovered that this agent can disrupt vascular formation by interfering with angiogenesis-associated genes including the genes encoding vascular endothelial growth factor Aa (vegfaa), vegfc, fms-related tyrosine kinase 1 (flt1), and flt4 in zebrafish embryos. These anti-angiogenic effects of flufenoxuron were further verified using a well-known angiogenesis model, namely human umbilical vein endothelial cells. In conclusion, our results suggest that flufenoxuron inhibits overall development and angiogenesis during embryogenesis.