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Computational Toxicology Research

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Experimental Approaches

The v-Embryo research project uses multiple experimental approaches and different types of data sources.

  • ToxCast: chemical screening data resulting from these fast, automated tests.
  • Embryonic Stem Cell Assays: cells from early embryos that have the potential to differentiate into any cell of the body.
  • Traditional prenatal studies: data from chronic, subchronic, reproductive and developmental animal studies. Much of this data is stored in ToxRefDB.
  • Zebrafish: hold promise for rapid screening of chemicals based on the potential to directly perturb developmental processes.
  • Developmental pathways: self-regulating genetic regulatory networks that pattern early development provide important information on the flow of molecular regulatory information at key stages of embryogenesis.
  • Virtual Liver Research: large-scale computer model of the complex "wiring diagram" of dynamic liver processes

Embryonic stem cell Assays

Chemcial ExposureCytotoxicity
  • Embryonic stem cells mimic normal development providing a high-throughput, in vitro platform for developmental toxicity testing.
  • Mouse (J1) and human (H1) embryonic stem cell lines spontaneously differentiate to multiple cell types, including cardiomyocytes (mesoderm derivative), when cultured in the absence of pluripotency factors.
  • Cardiomyocyte differentiation peaks after 9-14 days of differentiation and requires the normal function of all three primary cell types (endoderm, mesoderm,ectoderm).
  • Embryonic stem cells are exposed to multiple concentrations of chemicals during spontaneous differentiation.
  • Cardiomyocyte biomarker and cytotoxicity measurements are performed on the same cell populations at the end of a defined differentiation period and concentrations that produce a 50% change in differentiation and/or cytotoxicity are calculated.

Traditional Prenatal Studies

EPA's Toxicology Reference Database (ToxRefDB) houses conventional toxicity data from chronic, subchronic, reproductive and developmental animal studies. Records contain data on all toxicologically significant effects from legacy toxicity studies in rats, mice, rabbits among other test species. The infrastructure of v-Embryo™ includes a searchable document repository that builds on ToxRefDB complete with text-mining tools for semi-automated feature extraction.

Zebrafish

Zebrafish embryos hold promise for rapid screening of chemicals based on the potential to directly perturb developmental processes. Small eggs from zebrafish fit comfortably into a 96 or 384-well microtiter plate, enabling robotic handling and analyses of the developing embryo. Because zebrafish embryos are transparent the sequence of development may be directly observed without disturbing the embryo and consequently followed through precisely timed stages as the embryo advances from fertilized egg to a swimming fish larva. This progression occurs rapidly, in just 5 days, and recapitulates many of the same anatomical features, morphogenetic processes and cell signaling pathways used by the early human embryo. As such, Zebrafish embryos provide a powerful alternative to mammalian animal models in research aimed to document and classify the potential developmental toxicity of environmental chemicals and to model these dynamical processes in silico.

Developmental Pathways

Self-regulating genetic regulatory networks that pattern early development provide important information on the flow of molecular regulatory information at key stages of embryogenesis. Such information can be captured from public databases and literature resources using a combination of data-mining and text-mining tools. BioTapestry Exit EPA Disclaimer, an interactive web resource developed at the Institute for Systems Biology and California Institute of Technology, can be used to build these developmental gene regulatory networks and visualize them as standardized and extensible computational models or ‘wiring diagrams'. In a dynamic model, the relationships among factors in the wiring diagram can be made explicit by defining the relationships in terms of rates, quantities, or state changes.

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