6‐benzylaminopurine causes endothelial dysfunctions to human umbilical vein endothelial cells and exacerbates atorvastatin‐induced cerebral hemorrhage in zebrafish

Abstract 6‐benzylaminopurine (6‐BA), a multifunctional plant growth regulator, which is frequently used worldwide to improve qualities of various crops, is an important ingredient in production of “toxic bean sprouts.” Although there is no direct evidence of adverse effects, its hazardous effects, as well as joint toxicity with other chemicals, have received particular attention and aroused furious debate between proponents and environmental regulators. By use of human umbilical vein endothelial cells (HUVECs), adverse effects of 6‐BA to human‐derived cells were first demonstrated in this study. A total of 25–50 mg 6‐BA/L inhibited proliferation, migration, and formation of tubular‐like structures by 50% in vitro. Results of Western blot analyses revealed that exposure to 6‐BA differentially modulated the MAPK signal transduction pathway in HUVECs. Specifically, 6‐BA decreased phosphorylation of MEK and ERK, but increased phosphorylation of JNK and P38. In addition, 6‐BA exacerbated atorvastatin‐induced cerebral hemorrhage via increasing hemorrhagic occurrence by 60% and areas by 4 times in zebrafish larvae. In summary, 6‐BA elicited toxicity to the endothelial system of HUVECs and zebrafish. This was due, at least in part, to discoordination of MAPK signaling pathway, which should pose potential risks to the cerebral vascular system.