Real-Time Growth Kinetics Measuring Hormone Mimicry for ToxCast Chemicals in T-47D Human Ductal Carcinoma Cells

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• 作者：Daniel M. Rotroff ; David J. Dix ; Keith A. Houck ; Robert J. Kavlock ; Thomas B. Knudsen ; Matthew T. Martin ; David M. Reif ; Ann M. Richard ; Nisha S. Sipes ; Yama A. Abassi ; Can Jin ; Melinda Stampfl ; Richard S. Judson
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：July 15, 2013
• 年：2013
• 卷：26
• 期：7
• 页码：1097-1107
• 全文大小：533K
• 年卷期：v.26,no.7(July 15, 2013)
• ISSN：1520-5010

文摘

High-throughput screening (HTS) assays capable of profiling thousands of environmentally relevant chemicals for in vitro biological activity provide useful information on the potential for disrupting endocrine pathways. Disruption of the estrogen signaling pathway has been implicated in a variety of adverse health effects including impaired development, reproduction, and carcinogenesis. The estrogen-responsive human mammary ductal carcinoma cell line T-47D was exposed to 1815 ToxCast chemicals comprising pesticides, industrial chemicals, pharmaceuticals, personal care products, cosmetics, food ingredients, and other chemicals with known or suspected human exposure potential. Cell growth kinetics were evaluated using real-time cell electronic sensing. T-47D cells were exposed to eight concentrations (0.006鈥?00 渭M), and measurements of cellular impedance were repeatedly recorded for 105 h. Chemical effects were evaluated based on potency (concentration at which response occurs) and efficacy (extent of response). A linear growth response was observed in response to prototypical estrogen receptor agonists (17尾-estradiol, genistein, bisphenol A, nonylphenol, and 4-tert-octylphenol). Several compounds, including bisphenol A and genistein, induced cell growth comparable in efficacy to that of 17尾-estradiol, but with decreased potency. Progestins, androgens, and corticosteroids invoked a biphasic growth response indicative of changes in cell number or cell morphology. Results from this cell growth assay were compared with results from additional estrogen receptor (ER) binding and transactivation assays. Chemicals detected as active in both the cell growth and ER receptor binding assays demonstrated potencies highly correlated with two ER transactivation assays (r = 0.72; r = 0.70). While ER binding assays detected chemicals that were highly potent or efficacious in the T-47D cell growth and transactivation assays, the binding assays lacked sensitivity in detecting weakly active compounds. In conclusion, this cell-based assay rapidly detects chemical effects on T-47D growth and shows potential, in combination with other HTS assays, to detect environmentally relevant chemicals with potential estrogenic activity.