Nanoplastics exposure induces vascular malformation by interfering with the VEGFA/VEGFR pathway in zebrafish (Danio rerio).

The widespread accumulation and adverse effects of nanoplastics (NPs) are a growing concern for environmental and human health. However, the potential toxicological effects of nanoplastics, especially on vascular development, have not been well studied. In this study, the zebrafish model was utilized to systematically study the developmental toxicity of nanoplastics exposure at different concentrations with morphological, histological, and molecular levels. The results revealed developmental defects in zebrafish embryos after exposure to different concentrations of nanoplastics. Specifically, the morphological deformities, including pericardial oedema and spine curvature, as well as the abnormal body length and the rates of survival and hatching were induced after nanoplastics exposure in zebrafish embryos. In addition, we found that nanoplastics exposure could induce vascular malformation, including the ectopic sprouting of intersegmental vessels (ISVs), malformation of superficial ocular vessels (SOVs), and overgrowth of the common cardinal vein (CCV), as well as the disorganized vasculature of the subintestinal venous plexus (SIVP). Moreover, further study indicated that SU5416, a specific vascular endothelial growth factor receptor (VEGFR) inhibitor, partially rescued the nanoplastics exposure-impaired vasculature, suggesting that the VEGFA/VEGFR pathway might be associated with nanoplastics-induced vascular malformation in zebrafish embryos. Further quantitative polymerase chain reaction assays revealed that the mRNA levels of VEGFA/VEGFR pathway-related genes, including vegfa, nrp1, klf6a, flt1, fih-1, flk1, cldn5a, and rspo3, were altered in different groups, indicating that nanoplastics exposure interferes with the VEGFA/VEGFR pathway, thereby inducing vascular malformation during the early developmental stage in zebrafish embryos. Therefore, our findings illustrated that nanoplastics might induce vascular malformation by regulating VEGFA/VEGFR pathway-related genes at the early developmental stage in zebrafish.

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish.

BACKGROUND: Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. METHODS: We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. RESULTS: We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. CONCLUSION: Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.