| Quantitative high-throughput screening for chemical toxicity in a population-based in vitro model. | |
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MedLine Citation:
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PMID: 22268004 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A shift in toxicity testing from in vivo to in vitro may efficiently prioritize compounds, reveal new mechanisms, and enable predictive modeling. Quantitative high-throughput screening (qHTS) is a major source of data for computational toxicology, and our goal in this study was to aid in the development of predictive in vitro models of chemical-induced toxicity, anchored on interindividual genetic variability. Eighty-one human lymphoblast cell lines from 27 Centre d'Etude du Polymorphisme Humain trios were exposed to 240 chemical substances (12 concentrations, 0.26nM-46.0μM) and evaluated for cytotoxicity and apoptosis. qHTS screening in the genetically defined population produced robust and reproducible results, which allowed for cross-compound, cross-assay, and cross-individual comparisons. Some compounds were cytotoxic to all cell types at similar concentrations, whereas others exhibited interindividual differences in cytotoxicity. Specifically, the qHTS in a population-based human in vitro model system has several unique aspects that are of utility for toxicity testing, chemical prioritization, and high-throughput risk assessment. First, standardized and high-quality concentration-response profiling, with reproducibility confirmed by comparison with previous experiments, enables prioritization of chemicals for variability in interindividual range in cytotoxicity. Second, genome-wide association analysis of cytotoxicity phenotypes allows exploration of the potential genetic determinants of interindividual variability in toxicity. Furthermore, highly significant associations identified through the analysis of population-level correlations between basal gene expression variability and chemical-induced toxicity suggest plausible mode of action hypotheses for follow-up analyses. We conclude that as the improved resolution of genetic profiling can now be matched with high-quality in vitro screening data, the evaluation of the toxicity pathways and the effects of genetic diversity are now feasible through the use of human lymphoblast cell lines. |
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Authors:
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Eric F Lock; Nour Abdo; Ruili Huang; Menghang Xia; Oksana Kosyk; Shannon H O'Shea; Yi-Hui Zhou; Alexander Sedykh; Alexander Tropsha; Christopher P Austin; Raymond R Tice; Fred A Wright; Ivan Rusyn |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-01-19 |
Journal Detail:
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Title: Toxicological sciences : an official journal of the Society of Toxicology Volume: 126 ISSN: 1096-0929 ISO Abbreviation: Toxicol. Sci. Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-03-20 Completed Date: 2012-07-16 Revised Date: 2013-05-22 |
Medline Journal Info:
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Nlm Unique ID: 9805461 Medline TA: Toxicol Sci Country: United States |
Other Details:
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Languages: eng Pagination: 578-88 Citation Subset: IM |
Affiliation:
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University of North Carolina, Chapel Hill, North Carolina 27599, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis Cell Line Humans Models, Theoretical* Reproducibility of Results Toxicity Tests* |
| Grant Support | |
ID/Acronym/Agency:
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R01 ES015241/ES/NIEHS NIH HHS; Y2-ES-7020-01/ES/NIEHS NIH HHS |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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