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
-
- Neovascularization, Physiologic/drug effects*
- Animals
- Models, Animal
- Zebrafish
- Animals, Genetically Modified
- High-Throughput Screening Assays
- Environmental Pollutants/toxicity*
- Angiogenesis Inhibitors/toxicity*
- Cardiovascular System/drug effects*
- Cardiovascular System/embryology
- Embryonic Development/drug effects*
- Green Fluorescent Proteins/genetics
- Embryo, Nonmammalian/blood supply
- Embryo, Nonmammalian/drug effects*
- PubMed
- 28007540 Full text @ Reprod. Toxicol.
Citation
Tal, T., Kilty, C., Smith, A., LaLone, C., Kennedy, B., Tennant, A., McCollum, C.W., Bondesson, M., Knudsen, T., Padilla, S., Kleinstreuer, N. (2017) Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity. Reproductive toxicology (Elmsford, N.Y.). 70:70-81.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping