Lead acetate (PbAc) impairs blood-brain barrier in zebrafish via MMP-9/13-induced pericyte developmental defects

Lead (Pb), a persistent heavy metal, has caused widespread environmental contamination due to its extensive industrial use. Among its compounds, lead acetate (PbAc) is particularly hazardous in aqueous form, exhibiting neurotoxic potential. However, its toxic effects on the integrity of the blood-brain barrier (BBB) and the underlying mechanisms remain poorly understood. This study demonstrates that zebrafish embryos exposed to varying concentrations of PbAc exhibit dose-dependent morphological abnormalities, including growth retardation, delayed hatching, and cardiovascular dysfunction, along with pronounced neurobehavioral deficits in both embryonic and adult zebrafish. Live imaging analysis revealed that both acute and chronic exposure to different concentrations of PbAc can induce cerebral hemorrhage and BBB dysfunction. Additionally, PbAc selectively disrupted cerebral angiogenesis without affecting trunk intersegmental vessels and significantly reduced pericyte coverage within both cerebral and trunk vessels. Mechanistically, RNA sequencing and qPCR validation revealed significant upregulation of MMP-9 and MMP-13 in PbAc-exposed embryos. Pharmacological inhibition of MMP-9/13 using polygalacic acid significantly reduced cerebral hemorrhage and restored pericyte coverage, suggesting that these proteases mediate PbAc-induced cerebrovascular damage. Overall, our findings underscore the ecological and public health risks associated with lead contamination and provide a basis for future therapeutic strategies targeting MMPs to mitigate heavy metal toxicity.