title: Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity.
abstract: Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive pVDC signature was constructed from 124 U.S. EPA ToxCast high-throughput screening (HTS) assays and used to rank 1060 chemicals for their potential to disrupt vascular development. Thirty-seven compounds were selected for targeted testing in transgenic Tg(kdrl:EGFP) and Tg(fli1:EGFP) zebrafish embryos to identify chemicals that impair developmental angiogenesis. We hypothesized that zebrafish angiogenesis toxicity data would correlate with human cell-based and cell-free in vitro HTS ToxCast data. Univariate statistical associations used to filter HTS data based on correlations with zebrafish angiogenic inhibition in vivo revealed 132 total significant associations, 33 of which were already captured in the pVDC signature, and 689 non-significant assay associations. Correlated assays were enriched in cytokine and extracellular matrix pathways. Taken together, the findings indicate the utility of zebrafish assays to evaluate an HTS-based predictive toxicity signature and also provide an experimental basis for expansion of the pVDC signature with novel HTS assays.
authors.affiliation: U.S. EPA/ORD/NHEERL/ISTD, RTP, NC, USA. Electronic address: tal.tamara@epa.gov.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tal
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Kilty
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.affiliation: U.S. EPA/ORD/NHEERL/MED, Duluth, MN, USA.
authors.forename: Carlie
authors.initials: C
authors.lastname: LaLone
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Brendán
authors.initials: B
authors.lastname: Kennedy
authors.affiliation: U.S. EPA/ORD/NHEERL/ISTD, RTP, NC, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Tennant
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.
authors.forename: Catherine W
authors.initials: CW
authors.lastname: McCollum
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Bondesson
authors.affiliation: U.S. EPA/ORD/NCCT, RTP, NC, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knudsen
authors.affiliation: U.S. EPA/ORD/NHEERL/ISTD, RTP, NC, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Padilla
authors.affiliation: NIEHS/DNTP/NICEATM, RTP, NC, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D002319:Cardiovascular System / Q000187:drug effects* / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D049452:Green Fluorescent Proteins / Q000235:genetics; D057166:High-Throughput Screening Assays; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D004785:Environmental Pollutants; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Angiogenic inhibition; Predictive toxicology; Zebrafish