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A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor α in an MCF-7 Microarray Compendium
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-01-06 , DOI: 10.1021/acs.chemrestox.0c00243
John Rooney 1 , Natalia Ryan 1 , Jie Liu 1 , René Houtman 2 , Rinie van Beuningen 2 , Jui-Hua Hsieh 3 , Gregory Chang 4 , Shiuan Chen 4 , J Christopher Corton 1
Affiliation  

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.

中文翻译:

基因表达生物标志物鉴定 MCF-7 微阵列中雌激素受体 α 的化学调节剂

识别影响激素调节系统的化学物质将有助于预测内分泌干扰。在我们之前的研究中,发现 46 个基因生物标志物可以准确预测经过化学处理的 MCF-7 细胞中雌激素受体 (ER) α 的调节。在这里,通过筛选由~1600个代表暴露于~1200种化学物质的基因表达比较组成的微阵列概要,使用生物标志物鉴定了潜在的ERα调节剂。总共约 170 种化学物质被鉴定为潜在的 ERα 调节剂。在 Connectivity Map 2.0 集合中,预计有 75 种和 39 种化学物质会激活或抑制 ERα,其中分别包括 12 种和 6 种已知的 ERα 激动剂和拮抗剂/选择性 ERα 调节剂。在用于分别以激动剂或拮抗剂模式筛选 Tox21 10K 化学文库的 MCF-7 衍生细胞系中进行的 ERα 反式激活测定中,也鉴定了总数中的 19 个和 8 个具有活性。使用野生型和 ERα 缺失细胞中的全局和靶向基因表达、反式激活测定和无细胞 ERα 共调节剂相互作用测定,进一步检查了预测在 MCF-7 细胞中调节 ERα 的化学物质。被归类为弱和极弱激动剂的环境化学物质被证实可以激活 ERα,包括芹菜素、山奈酚和氧苯酮。新型激活剂包括地高辛、萘丁美酮、伊维菌素和六种孕激素。新型抑制剂包括依米丁、米非司酮、氯硝柳胺和前西拉定。我们的策略将有助于在未来的高通量转录组筛选中识别环境相关的 ERα 调节剂。
更新日期:2021-02-15
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