title: Environmental impact on vascular development predicted by high-throughput screening.
abstract: BACKGROUND
  Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease.
  
  
  OBJECTIVE
  We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling.
  
  
  METHODS
  ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles.
  
  
  RESULTS
  Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here.
  
  
  CONCLUSIONS
  We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.
authors.affiliation: National Center for Computational Toxiciology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA. kleinstreuer.nicole@epa.gov
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kleinstreuer
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.forename: Nisha S
authors.initials: NS
authors.lastname: Sipes
authors.forename: Amar V
authors.initials: AV
authors.lastname: Singh
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Chandler
authors.forename: Rob
authors.initials: R
authors.lastname: Dewoskin
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects* / Q000196:embryology*; D019295:Computational Biology; D016208:Databases, Factual; D004785:Environmental Pollutants / Q000032:analysis / Q000145:classification* / Q000276:immunology / Q000633:toxicity*; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D023421:Models, Animal; D015999:Multivariate Analysis; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D054852:Small Molecule Libraries / Q000032:analysis / Q000145:classification / Q000633:toxicity; D013045:Species Specificity; D014116:Toxicology / Q000379:methods*; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D004785:Environmental Pollutants; D054852:Small Molecule Libraries