Identification of vascular disruptor compounds by analysis in zebrafish embryos and mouse embryonic endothelial cells

Reprod Toxicol. 2017 Jun;70:60-69. doi: 10.1016/j.reprotox.2016.11.005. Epub 2016 Nov 10.

Abstract

To identify vascular disruptor compounds (VDCs), this study utilized an in vivo zebrafish embryo vascular model in conjunction with a mouse endothelial cell model to screen a subset of the U.S. Environmental Protection Agency (EPA) ToxCast Phase I chemical inventory. In zebrafish, 161 compounds were screened and 34 were identified by visual inspection as VDCs, of which 28 were confirmed as VDCs by quantitative image analysis. Testing of the zebrafish VDCs for their capacity to inhibit endothelial tube formation in the murine yolk-sac-derived endothelial cell line C166 identified 22 compounds that both disrupted zebrafish vascular development and murine endothelial in vitro tubulogenesis. Putative molecular targets for the VDCs were predicted using EPA's Toxicological Prioritization Index tool and a VDC signature based on a proposed adverse outcome pathway for developmental vascular toxicity. In conclusion, our screening approach identified 22 novel VDCs, some of which were active at nanomolar concentrations.

Keywords: Angiogenesis; Mouse endothelial cells; Vascular development; Vascular disruptor compounds; Zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cardiovascular System / drug effects*
  • Cardiovascular System / embryology
  • Cell Line
  • Embryo, Mammalian / blood supply
  • Embryo, Mammalian / drug effects
  • Embryo, Nonmammalian / blood supply
  • Embryo, Nonmammalian / drug effects
  • Embryonic Development / drug effects*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology
  • Environmental Pollutants / toxicity*
  • Green Fluorescent Proteins / genetics
  • Mice
  • Zebrafish

Substances

  • Environmental Pollutants
  • Green Fluorescent Proteins