title: Quantitative high-throughput screening for chemical toxicity in a population-based in vitro model.
abstract: 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.
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Lock
authors.forename: Nour
authors.initials: N
authors.lastname: Abdo
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Shannon H
authors.initials: SH
authors.lastname: O'Shea
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Zhou
authors.forename: Alexander
authors.initials: A
authors.lastname: Sedykh
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008962:Models, Theoretical; D015203:Reproducibility of Results; D018675:Toxicity Tests