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Modeling the disruption of vascular development in a Virtual Embryo using ToxCast HTS Bioactivity Profiles
Citation:
KLEINSTREUER, N., D. J. DIX, R. JUDSON, R. J. KAVLOCK, M. ROUNTREE, N. SIPES, R. DEWOSKIN, A. V. SINGH, R. SPENCER, AND T. B. KNUDSEN. Modeling the disruption of vascular development in a Virtual Embryo using ToxCast HTS Bioactivity Profiles. Presented at Society of Toxicology Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
ToxCast project
Description:
Blood vessel formation is an important aspect of embryo development and teratogenesis. Recent studies address the signaling networks responsible for vasculogenesis and how they might be targeted by certain chemicals. For example, disruption of vasculogenesis and angiogenesis pathways, including vascular endothelial growth factor (VEGF) and platelet derived growth factor receptor (PDGFRb), occurs during thalidomide embryopathy to alter vascular cell recruitment and proliferation during key stages of embryogenesis. In a preliminary analysis of ToxCast high-throughput screening (HTS) data from 467 assays and 309 chemicals, a number of environmental chemicals had measureable effects in vitro assays for specific targets or cellular processes important to vasculogenesis and angiogenesis. A preliminary predictive signature built from ToxCast data for several in vivo developmental endpoints from EPA’s ToxRefDB database includes a pro-inflammatory / anti-angiogenic cytokine signaling network (CXCL10, CCL2, VCAM1, CD40, MMP1), and the plasminogen activating system (PAS) network of enzymes and growth factors mediating matrix remodeling and local signaling during blood vessel growth. We hypothesize that embryonic microvascular networks are targets for certain environmental chemicals with teratogenic potential. EPA’s Virtual Embryo project is building in silico models of morphogenesis to test chemical dose-response hypotheses by simulating developmental toxicity effects. To better characterize molecular mechanisms of vascular network development, a systems-based model is constructed testing flow-signal interactions and implementing HTS predictive signatures for developmental defects associated with disturbance of morphogenetic signals, nutrients, and metabolic products. The model is developed in CompuCell3D software and supplemented through semi-automatic vasculogenesis-angiogenesis knowledgebase creation. [This work is approved by EPA but does not reflect official Agency policy].
URLs/Downloads:
Modeling the disruption of vascular development in a Virtual Embryo using ToxCast HTS Bioactivity Profiles (slides) (PDF, NA pp, 1501 KB, about PDF)Modeling the disruption of vascular development in a Virtual Embryo using ToxCast HTS Bioactivity Profiles (abs) (PDF, NA pp, 12 KB, about PDF)