PUBLICATION

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Authors
Tal, T., Kilty, C., Smith, A., LaLone, C., Kennedy, B., Tennant, A., McCollum, C.W., Bondesson, M., Knudsen, T., Padilla, S., Kleinstreuer, N.
ID
ZDB-PUB-161224-12
Date
2017
Source
Reproductive toxicology (Elmsford, N.Y.)   70: 70-81 (Journal)
Registered Authors
Kennedy, Breandan N.
Keywords
Angiogenic inhibition, predictive toxicology, zebrafish
MeSH Terms
  • Angiogenesis Inhibitors/toxicity*
  • Animals
  • Animals, Genetically Modified
  • Cardiovascular System/drug effects*
  • Cardiovascular System/embryology
  • Embryo, Nonmammalian/blood supply
  • Embryo, Nonmammalian/drug effects*
  • Embryonic Development/drug effects*
  • Environmental Pollutants/toxicity*
  • Green Fluorescent Proteins/genetics
  • High-Throughput Screening Assays
  • Models, Animal
  • Neovascularization, Physiologic/drug effects*
  • Zebrafish
PubMed
28007540 Full text @ Reprod. Toxicol.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping