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Phenotypic Screening of Primary Human Cell Culture Systems to Identify Potential for Compound Toxicity (CHI Phenotypic Screening)
Houck, K. Phenotypic Screening of Primary Human Cell Culture Systems to Identify Potential for Compound Toxicity (CHI Phenotypic Screening). Presented at Cambridge Healthtech Institute’s Phenotypic Screening, San Diego, CA, January 26 - 27, 2015. https://doi.org/10.23645/epacomptox.5080015
invited presentation at phenotypic screening for toxicity conference.
Addressing safety aspects of drugs and environmental chemicals has historically been undertaken through animal testing. However, the quantity of chemicals needing assessment and the challenge of species extrapolation require development of alternative approaches. Assessing phenotypic changes in human primary cells in vitro provides a means to evaluate chemical effects in physiologically relevant systems. We have evaluated complex primary human cell systems by screening chemicals for interactions disrupting physiologically important pathways. Chemical-response signatures derived from 87 endpoints covering molecular functions relevant to toxic and therapeutic pathways were generated for a large library of environmental chemicals, reference pharmaceuticals and failed drugs. Computational assessment of profiling data identified abundant chemical clusters showing polypharmacology and potential off-target effects. These clusters contained diverse mechanistic activity encompassing kinase, TNFα, phosphodiesterases and Hsp90 inhibitors; aryl hydrocarbon, estrogen, and glucocorticoid receptor modulators; disruptors of mitochondrial and tubulin function; histamine antagonists; and statins. Our results demonstrate use of the extensive biological complexity inherent in human primary cells to identify potential toxicity targets, novel therapeutic applications and/or toxicological liabilities of chemicals. This abstract does not necessarily represent U.S. EPA policy.