title: Immediate and long-term consequences of vascular toxicity during zebrafish development.
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.
authors.affiliation: Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States. Electronic address: tal.tamara@epa.gov.
authors.forename: T L
authors.initials: TL
authors.lastname: Tal
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, United States.
authors.forename: C W
authors.initials: CW
authors.lastname: McCollum
authors.affiliation: Gulf Ecology Division, NHEERL, U.S. EPA, Gulf Breeze, FL, United States.
authors.forename: P S
authors.initials: PS
authors.lastname: Harris
authors.affiliation: Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States.
authors.forename: J
authors.initials: J
authors.lastname: Olin
authors.affiliation: National Center for Computational Toxicology, US EPA, RTP, NC, United States.
authors.forename: N
authors.initials: N
authors.lastname: Kleinstreuer
authors.affiliation: Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States.
authors.forename: C E
authors.initials: CE
authors.lastname: Wood
authors.affiliation: Department of Computer Science, University of Houston, Houston, TX, United States.
authors.forename: C
authors.initials: C
authors.lastname: Hans
authors.affiliation: Department of Engineering Technology, University of Houston, Houston TX, United States.
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Computer Science, University of Houston, Houston, TX, United States; Department of Engineering Technology, University of Houston, Houston TX, United States.
authors.forename: F A
authors.initials: FA
authors.lastname: Merchant
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, United States.
authors.forename: M
authors.initials: M
authors.lastname: Bondesson
authors.affiliation: National Center for Computational Toxicology, US EPA, RTP, NC, United States.
authors.forename: T B
authors.initials: TB
authors.lastname: Knudsen
authors.affiliation: Integrated Systems Toxicology Division, NHEERL, U.S. EPA, RTP, NC, United States.
authors.forename: S
authors.initials: S
authors.lastname: Padilla
authors.affiliation: Gulf Ecology Division, NHEERL, U.S. EPA, Gulf Breeze, FL, United States.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hemmer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000187:drug effects / Q000196:embryology*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology*; D047108:Embryonic Development / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D010793:Phthalazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C404768:vatalanib; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Adverse outcome pathway; EGFR; Intersegmental vessel; VEGFR2