Citation:

Tal, T., C. McCollum, P. Harris, J. Olin, N. Kleinstreuer, C. Wood, C. Hans, S. Shah, F. Merchant, M. Bondesson, T. Knudsen, S. Padilla, AND M. Hemmer. Immediate and long-term consequences of vascular toxicity during zebrafish development. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 48:51-61, (2014).

Impact/Purpose:

This study was designed to develop and evaluate a quantitative model of vascular toxicity in embroyonic zebrafish. In comparison to previous reports that rely on more qualitative metrics like the perfect of normal vessels, we developed a quantitative assay capable of detecting relatively subtle changes (~8%) in intersegmental vessel length relatative to control sprouts. This study fulfills a RAP requirement in CSS 2.2.2 Product 3. Further, it allows us to fulfill additional requirements in CSS 2.2.2 Products 1 and 3 related to screening a 38-chemical test set to test predictive toxicology rankings by the vascular toxicity predictive signature.

Description:

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 developed a quantitative assay in transgenic zebrafish and evaluated the assay 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 disrupton of the presumed targets for these inhibitors produce adverse outcomes at advanced life stages.

Record Details: