A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor α in an MCF-7 Microarray Compendium
| Autor: | J. Christopher Corton, Shiuan Chen, Gregory Chang, Natalia Ryan, Rinie van Beuningen, John P. Rooney, Jui-Hua Hsieh, René Houtman, Jie Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Agonist
Microarray medicine.drug_class Estrogen receptor 010501 environmental sciences Toxicology 01 natural sciences Chemical library Transcriptome 03 medical and health sciences chemistry.chemical_compound Transactivation Estrogen Receptor Modulators Gene expression Biomarkers Tumor Tumor Cells Cultured medicine Humans 030304 developmental biology 0105 earth and related environmental sciences 0303 health sciences Chemistry Gene Expression Profiling Estrogen Receptor alpha General Medicine MCF-7 Cells Cancer research Biomarker (medicine) Female |
| Zdroj: | Chemical Research in Toxicology. 34:313-329 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.0c00243 |
| Popis: | Identification of chemicals that affect hormone-regulated systems will help to predict endocrine disruption. In our previous study, a 46 gene biomarker was found to be an accurate predictor of estrogen receptor (ER) α modulation in chemically treated MCF-7 cells. Here, potential ERα modulators were identified using the biomarker by screening a microarray compendium consisting of ∼1600 gene expression comparisons representing exposure to ∼1200 chemicals. A total of ∼170 chemicals were identified as potential ERα modulators. In the Connectivity Map 2.0 collection, 75 and 39 chemicals were predicted to activate or suppress ERα, and they included 12 and six known ERα agonists and antagonists/selective ERα modulators, respectively. Nineteen and eight of the total number were also identified as active in an ERα transactivation assay carried out in an MCF-7-derived cell line used to screen the Tox21 10K chemical library in agonist or antagonist modes, respectively. Chemicals predicted to modulate ERα in MCF-7 cells were examined further using global and targeted gene expression in wild-type and ERα-null cells, transactivation assays, and cell-free ERα coregulator interaction assays. Environmental chemicals classified as weak and very weak agonists were confirmed to activate ERα including apigenin, kaempferol, and oxybenzone. Novel activators included digoxin, nabumetone, ivermectin, and six progestins. Novel suppressors included emetine, mifepristone, niclosamide, and proscillaridin. Our strategy will be useful to identify environmentally relevant ERα modulators in future high-throughput transcriptomic screens. |
| Databáze: | OpenAIRE |
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