Cadmium-induced dysfunction of the blood-brain barrier depends on ROS-mediated inhibition of PTPase activity in zebrafish

Highlights: • Cdcl₂ induced cerebral and retinal hemorrhage in zebrafish. • Cdcl₂ impaired blood-brain barrier (BBB) maturation and increased BBB permeability in zebrafish. • Cdcl₂ induced morphological alteration of adherens junction (AJ) and tight junction (TJ) proteins in vitro and in vivo. • Disruption of endothelial cell-cell junctions is dependent on inhibition of protein tyrosine phosphatase (PTPase) activity mediated by Cdcl₂-induced ROS. Increasing evidence has demonstrated that cadmium accumulation in the blood increases the risk of neurological diseases. However, how cadmium breaks through the blood-brain barrier (BBB) and is transferred from the blood circulation into the central nervous system is still unclear. In this study, we examined the toxic effect of cadmium chloride (CdCl₂) on the development and function of BBB in zebrafish. CdCl₂ exposure induced cerebral hemorrhage, increased BBB permeability and promoted abnormal vascular formation by promoting VEGF production in zebrafish brain. Furthermore, in vivo and in vitro experiments showed that CdCl₂ altered cell-cell junctional morphology by disrupting the proper localization of VE-cadherin and ZO-1. The potential mechanism involved in the inhibition of protein tyrosine phosphatase (PTPase) mediated by cadmium-induced ROS was confirmed with diphenylene iodonium (DPI), a ROS production inhibitor. Together, these data indicate that BBB is a critical target of cadmium toxicity and provide in vivo etiological evidence of cadmium-induced neurovascular disease in a zebrafish BBB model.