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

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

Author information

1
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
2
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
3
Department of Computer Science, University of Houston, Houston, TX 77204, USA.
4
NIEHS/DNTP/NICEATM, RTP, NC 27560, USA.
5
U.S. EPA/ORD/ISTD, RTP, NC 27711, USA.
6
U.S. EPA/ORD/NCCT RTP, NC 27711, USA.
7
Department of Computer Science, University of Houston, Houston, TX 77204, USA; Department of Engineering Technology, University of Houston, Houston, TX 77204, USA.
8
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA; Department of Biosciences and Nutrition, Novum, Karolinska Institutet, 141 83 Stockholm, Sweden.
9
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA. Electronic address: mbondessonbolin@uh.edu.

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

PMID:
27838387
PMCID:
PMC5425326
DOI:
10.1016/j.reprotox.2016.11.005
[Indexed for MEDLINE]
Free PMC Article

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