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Use of Primary Human Cell Systems for Creating Predictive Toxicology Profiles
Citation:
HOUCK, K. A., D. J. DIX, AND E. L. Berg. Use of Primary Human Cell Systems for Creating Predictive Toxicology Profiles. Presented at Annual Society of Biomolecular Sciences Meeting, Lille, FRANCE, April 26 - 30, 2009.
Impact/Purpose:
ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, cAMP elevators, inhibitors of tubulin function, ER stress-inducers or NFB pathway inhibitors were identified based on this BioMAP analysis. Such bioactivity profiling and analysis may yield important information about the cellular activity of drug candidates as well as environmental chemicals, facilitating better prediction of potential in vivo toxicities.
Description:
Use of cellular regulatory networks to detect and distinguish effects of compounds with a broad range of on- and off-target mechanisms and biological processes provides an opportunity to understand toxicity mechanisms of action. Here we use the Biologically Multiplexed Activity Profiling (BioMAP) human primary cell system assays to characterize effects relevant to human tissue and inflammatory disease biology, we screened 320 environmental chemicals with well-characterized in vivo toxicities that constitute the EPA’s ToxCast library. The 320 chemicals were assayed at four concentrations in eight BioMAP systems, with a total of 87 different assay endpoints resulting in over 100,000 data points. The ToxCast compounds were classified on their ability to cause overt cytotoxicity in specific primary human cell types as well as activity mechanism class based on comparisons to activity profiles of BioMAP reference compounds.