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Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors

Environmental health perspectives, 2011-08, Vol.119 (8), p.1142-1148 [Peer Reviewed Journal]

2015 INIST-CNRS ;COPYRIGHT 2011 National Institute of Environmental Health Sciences ;COPYRIGHT 2011 National Institute of Environmental Health Sciences ;Copyright National Institute of Environmental Health Sciences Aug 2011 ;2011 ;ISSN: 0091-6765 ;EISSN: 1552-9924 ;DOI: 10.1289/ehp.1002952 ;PMID: 21543282 ;CODEN: EVHPAZ

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Title:
Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors
Author: Huang, Ruili ; Xia, Menghang ; Cho, Ming-Hsuang ; Sakamuru, Srilatha ; Shinn, Paul ; Houck, Keith A. ; Dix, David J. ; Judson, Richard S. ; Witt, Kristine L. ; Kaylock, Robert J. ; Tice, Raymond R. ; Austin, Christopher P.
Subjects: Agonists ; Biological and medical sciences ; Cell Line ; Cell receptors ; Chemical hazards ; Chemicals ; Cytotoxicity ; Environment. Living conditions ; Environmental agencies ; Environmental aspects ; Environmental health ; Environmental Pollutants - toxicity ; Estrogen Receptor alpha - metabolism ; Fragile X Mental Retardation Protein ; Genomics ; Health aspects ; Humans ; Libraries ; Ligands ; Liver X Receptors ; Medical sciences ; Nuclear receptors ; Orphan Nuclear Receptors - agonists ; Orphan Nuclear Receptors - antagonists & inhibitors ; Orphan Nuclear Receptors - metabolism ; Peroxisome Proliferator-Activated Receptors - agonists ; Peroxisome Proliferator-Activated Receptors - antagonists & inhibitors ; Peroxisome Proliferator-Activated Receptors - metabolism ; Physiological aspects ; PPAR gamma - antagonists & inhibitors ; PPAR gamma - metabolism ; Public health. Hygiene ; Public health. Hygiene-occupational medicine ; Receptors ; Receptors, Androgen - metabolism ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors ; Receptors, Cytoplasmic and Nuclear - metabolism ; Receptors, Thrombin - agonists ; Receptors, Thrombin - antagonists & inhibitors ; Receptors, Thrombin - metabolism ; Retinoid X Receptor alpha - agonists ; Retinoid X Receptor alpha - antagonists & inhibitors ; Retinoid X Receptor alpha - metabolism ; Toxicology
Is Part Of: Environmental health perspectives, 2011-08, Vol.119 (8), p.1142-1148
Description: Background: The large and increasing number of chemicals released into the environment demands 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 generating data from screening large chemical libraries using 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 10 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: We determined the assays to be appropriate in terms of biological relevance. We found better concordance for replicate compounds for the agonist-mode than for 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.
Publisher: Research Triangle Park, NC: National Institute of Environmental Health Sciences
Language: English
Identifier: ISSN: 0091-6765
EISSN: 1552-9924
DOI: 10.1289/ehp.1002952
PMID: 21543282
CODEN: EVHPAZ
Source: U.S. Government Documents
MEDLINE
PubMed Central
ProQuest Central
DOAJ Directory of Open Access Journals

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Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors

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