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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tal, T; Kilty, C; Smith, A; LaLone, C; Kennedy, B; Tennant, A; McCollum, CW; Bondesson, M; Knudsen, T; Padilla, S; Kleinstreuer, N

Published Date

  • June 2017

Published In

Volume / Issue

  • 70 /

Start / End Page

  • 70 - 81

PubMed ID

  • 28007540

Pubmed Central ID

  • PMC6282194

Electronic International Standard Serial Number (EISSN)

  • 1873-1708

International Standard Serial Number (ISSN)

  • 0890-6238

Digital Object Identifier (DOI)

  • 10.1016/j.reprotox.2016.12.004

Language

  • eng