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

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; BG...

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Main Authors:	Huang, Ruili, Sakamuru, Srilatha, Martin, Matt T., Reif, David M., Judson, Richard S., Houck, Keith A., Casey, Warren, Hsieh, Jui-Hua, Shockley, Keith R., Ceger, Patricia, Fostel, Jennifer, Witt, Kristine L., Tong, Weida, Rotroff, Daniel M., Zhao, Tongan, Shinn, Paul, Simeonov, Anton, Dix, David J., Austin, Christopher P., Kavlock, Robert J., Tice, Raymond R., Xia, Menghang
Format:	Online
Language:	English
Published:	Nature Publishing Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092345/

id	pubmed-4092345
recordtype	oai_dc
spelling	pubmed-40923452014-07-11 Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang Article 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. Nature Publishing Group 2014-07-11 /pmc/articles/PMC4092345/ /pubmed/25012808 http://dx.doi.org/10.1038/srep05664 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang
spellingShingle	Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
author_facet	Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang
author_sort	Huang, Ruili
title	Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
title_short	Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
title_full	Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
title_fullStr	Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
title_full_unstemmed	Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
title_sort	profiling of the tox21 10k compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway
description	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.
publisher	Nature Publishing Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092345/
_version_	1613111582089281536

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

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