Immediate and long-term consequences of vascular toxicity during zebrafish development

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 48; pp. 51 - 61
• Main Authors: Tal, T.L., McCollum, C.W., Harris, P.S., Olin, J., Kleinstreuer, N., Wood, C.E., Hans, C., Shah, S., Merchant, F.A., Bondesson, M., Knudsen, T.B., Padilla, S., Hemmer, M.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014
• Subjects: Adverse outcome pathway; Angiogenesis Inhibitors - pharmacology; Animals; Animals, Genetically Modified; Blood Vessels - drug effects; Blood Vessels - embryology; EGFR; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - embryology; Embryonic Development - drug effects; Embryonic Development - physiology; Intersegmental vessel; Phthalazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Tyrphostins - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR2; Zebrafish - embryology; VEGFR2; AOP; DMSO; DAPI; ISV; AER; EGFR; GFP; Intersegmental vessel; TK; VEGFR; TM; dpf; hpf; Adverse outcome pathway
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2014.05.014

•Developmental exposure to the VEGFR2 inhibitor PTK787 produces concentration-dependent, vascular-specific toxicity in embryonic zebrafish.•Exposure to the EGFR inhibitor AG1478 triggers caudal and pectoral fin malformations at lower concentrations than those that induce abnormal intersegmental vessel development.•Embryonic vascular malformations persist in 5 day post fertilization (dpf) larvae developmentally exposed to PTK787 or AG1478.•Severe vascular toxicity during embryogenesis is accompanied by overt malformations that result in increased mortality at the transition to independent feeding. Proper formation of the vascular system is necessary for embryogenesis, and chemical disruption of vascular development may be a key event driving developmental toxicity. In order to test the effect of environmental chemicals on this critical process, we evaluated a quantitative assay in transgenic zebrafish using angiogenesis inhibitors that target VEGFR2 (PTK787) or EGFR (AG1478). Both PTK787 and AG1478 exposure impaired intersegmental vessel (ISV) sprouting, while AG1478 also produced caudal and pectoral fin defects at concentrations below those necessary to blunt ISV morphogenesis. The functional consequences of vessel toxicity during early development included decreased body length and survival in juvenile cohorts developmentally exposed to inhibitor concentrations sufficient to completely block ISV sprouting angiogenesis. These data show that concentration-dependent disruption of the presumed targets for these inhibitors produce adverse outcomes at advanced life stages.