title: Identification of vascular disruptor compounds by analysis in zebrafish embryos and mouse embryonic endothelial cells.
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.
authors.affiliation: Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
authors.forename: Catherine W
authors.initials: CW
authors.lastname: McCollum
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Conde-Vancells
authors.affiliation: Department of Computer Science, University of Houston, Houston, TX 77204, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Hans
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Vazquez-Chantada
authors.affiliation: NIEHS/DNTP/NICEATM, RTP, NC 27560, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
authors.affiliation: U.S. EPA/ORD/ISTD, RTP, NC 27711, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tal
authors.affiliation: U.S. EPA/ORD/NCCT RTP, NC 27711, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knudsen
authors.affiliation: Department of Computer Science, University of Houston, Houston, TX 77204, USA.
authors.forename: Shishir S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Department of Computer Science, University of Houston, Houston, TX 77204, USA; Department of Engineering Technology, University of Houston, Houston, TX 77204, USA.
authors.forename: Fatima A
authors.initials: FA
authors.lastname: Merchant
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: 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.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Cabrera
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Bondesson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002319:Cardiovascular System / Q000187:drug effects* / Q000196:embryology; D002460:Cell Line; D004622:Embryo, Mammalian / Q000098:blood supply / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004785:Environmental Pollutants / Q000633:toxicity*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D015027:Zebrafish
chemical_list: D004785:Environmental Pollutants; D049452:Green Fluorescent Proteins
keywords: Angiogenesis; Mouse endothelial cells; Vascular development; Vascular disruptor compounds; Zebrafish