title: Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway.
abstract: The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ERα) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ERα (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ERα β-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ERα agonists and antagonists was evaluated using a set of 39 reference compounds with known ERα activity. Although both assays demonstrated adequate (i.e. >80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ERα binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERα active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERα signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals.
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Sakamuru
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Matt T
authors.initials: MT
authors.lastname: Martin
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Casey
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Jui-Hua
authors.initials: JH
authors.lastname: Hsieh
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Shockley
authors.affiliation: ILS Inc., Research Triangle Park, NC 27709, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ceger
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fostel
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Witt
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Tongan
authors.initials: T
authors.lastname: Zhao
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
mesh_terms: D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008024:Ligands; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D054852:Small Molecule Libraries