Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors.

Background: The large and increasing number of chemicals released into the environment demand more efficient and cost effective approaches for assessing environmental chemical toxicity. The U.S. Tox21 program has responded to this challenge by proposing alternative strategies for toxicity testing, among which the quantitative high-throughput screening (qHTS) paradigm has been adopted as the primary tool for data generation on large chemical libraries against a wide spectrum of assays. Objectives: The goal of this study was to develop methods to evaluate the data generated from these assays to guide future assay selection and prioritization for the Tox21 program. Methods: We examined the data from the Tox21 pilot phase collection of approximately 3,000 environmental chemicals profiled in qHTS format against a panel of ten human nuclear receptors (AR, ERα, FXR, GR, LXRβ, PPARγ, PPARδ, RXRα, TRβ, and VDR) for reproducibility, concordance of biological activity profiles with sequence homology of the receptor ligand binding domains, and structure-activity relationships. Results: The assays were determined to be appropriate in terms of biological relevance. Better concordance for replicate compounds was found for the agonist mode than the antagonist mode assays, likely due to interference of cytotoxicity in the latter assays. This exercise also enabled us to formulate data driven strategies for discriminating true signals from artifacts, and to prioritize assays based on data quality. Conclusions: The results demonstrate the feasibility of qHTS to identify the potential for environmentally relevant chemicals to interact with key toxicity pathways related to human disease induction.