Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-06

AUTHORS

Nicole C Kleinstreuer, Jian Yang, Ellen L Berg, Thomas B Knudsen, Ann M Richard, Matthew T Martin, David M Reif, Richard S Judson, Mark Polokoff, David J Dix, Robert J Kavlock, Keith A Houck

ABSTRACT

Addressing the safety aspects of drugs and environmental chemicals has historically been undertaken through animal testing. However, the quantity of chemicals in need of assessment and the challenges of species extrapolation require the development of alternative approaches. Our approach, the US Environmental Protection Agency's ToxCast program, utilizes a large suite of in vitro and model organism assays to interrogate important chemical libraries and computationally analyze bioactivity profiles. Here we evaluated one component of the ToxCast program, the use of primary human cell systems, by screening for chemicals that disrupt physiologically important pathways. Chemical-response signatures for 87 endpoints covering molecular functions relevant to toxic and therapeutic pathways were generated in eight cell systems for 641 environmental chemicals and 135 reference pharmaceuticals and failed drugs. Computational clustering of the profiling data provided insights into the polypharmacology and potential off-target effects for many chemicals that have limited or no toxicity information. The endpoints measured can be closely linked to in vivo outcomes, such as the upregulation of tissue factor in endothelial cell systems by compounds linked to the risk of thrombosis in vivo. Our results demonstrate that assaying complex biological pathways in primary human cells can identify potential chemical targets, toxicological liabilities and mechanisms useful for elucidating adverse outcome pathways. More... »

PAGES

583-591

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nbt.2914

DOI

http://dx.doi.org/10.1038/nbt.2914

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003341681

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24837663


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