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Pathway Profiling and Tissue Modeling Using ToxCast HTS Data
Citation:
KNUDSEN, T. B. Pathway Profiling and Tissue Modeling Using ToxCast HTS Data. Presented at Teratology Society Annual Meeting - ILSI-HESI Symposium: 21st Century Developmental Toxicology, Louisville, KY, June 26 - 30, 2010.
Impact/Purpose:
The project aligns with the federal Tox21c consortium ramping up to test ~10,000 chemical compounds by in vitro profiling.
Description:
High-throughput screening (HTS) and high-content screening (HCS) assays are providing data-rich studies to probe and profile the direct cellular effects of thousands of chemical compounds in commerce or potentially entering the environment. In vitro profiling may compare unknown bioactivities against reference compounds of well-characterized activity or else be interrogated in different ways, looking for novel and predictive signatures of in vivo toxicities. EPA’s ToxCast™ project has generated HTS and HCS data on 309 environmental chemicals across 467 in vitro assays. Proof-of principle (Phase-I) addressed mostly pesticidal and anti-microbial chemicals with rich in vivo animal testing data culled from EPA’s ToxRefDB database. The assays cover diverse biochemical activities, receptor binding activities, reporter gene activation and gene expression profiles, stress-response indicators, and perturbation in cell state and cellular function. In addition, the Phase-I assay space was expanded to monitor susceptibility in zebrafish embryos and pathways of differentiation in mouse embryonic stem cells. Machine-learning is used to identify patterns of biological activity and build predictive signatures of toxicity for chemical prioritization. A key aspect to this strategy is the integration of HTS/HCS data into canonical pathways for developmental signaling and cellular regulation. Several challenges face technology development such as correlating in vitro concentration-response with internal dose-response kinetics in vivo, understanding how in vitro bioactivity profiles extrapolate from one cell-type or technology platform to another, and linking individual targets of in vitro bioactivity into pathways of developmental toxicity. Computer simulators that reconstruct an emergent morphogenetic series of events can help extrapolate predictive signatures to different tissues, stages, doses, species, and exposures. Such multicellular models are a goal of EPA’s Virtual Embryo. The project aligns with the federal Tox21c consortium ramping up to test ~10,000 chemical compounds by in vitro profiling. [This work is approved by EPA but does not reflect official Agency policy].