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Sci Rep. 2014 Jul 11;4:5664. doi: 10.1038/srep05664.

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway.

Author information

1
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
2
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
3
Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
4
ILS Inc., Research Triangle Park, NC 27709, USA.
5
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.

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.

PMID:
25012808
PMCID:
PMC4092345
DOI:
10.1038/srep05664
[Indexed for MEDLINE]
Free PMC Article

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