title: Chemical genomics profiling of environmental chemical modulation of human nuclear receptors.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: National Institutes of Health Chemical Genomics Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-3370, USA. huangru@mail.nih.gov
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Ming-Hsuang
authors.initials: MH
authors.lastname: Cho
authors.forename: Srilatha
authors.initials: S
authors.lastname: Sakamuru
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Witt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
mesh_terms: D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha; D051860:Fragile X Messenger Ribonucleoprotein 1; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D018179:Receptors, Thrombin; D047490:Retinoid X Receptor alpha