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Reprod Toxicol. 2014 Sep;48:51-61. doi: 10.1016/j.reprotox.2014.05.014. Epub 2014 Jun 4.

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

Author information

1
Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States. Electronic address: tal.tamara@epa.gov.
2
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, United States.
3
Gulf Ecology Division, NHEERL, U.S. EPA, Gulf Breeze, FL, United States.
4
Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States.
5
National Center for Computational Toxicology, US EPA, RTP, NC, United States.
6
Department of Computer Science, University of Houston, Houston, TX, United States.
7
Department of Engineering Technology, University of Houston, Houston TX, United States.
8
Department of Computer Science, University of Houston, Houston, TX, United States; Department of Engineering Technology, University of Houston, Houston TX, United States.

Abstract

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.

KEYWORDS:

Adverse outcome pathway; EGFR; Intersegmental vessel; VEGFR2

PMID:
24907688
DOI:
10.1016/j.reprotox.2014.05.014
[Indexed for MEDLINE]
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