Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems
Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems
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DOI：
10.1177/1087057109345525
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发表时间：
2009-10-01
影响因子：
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通讯作者：
Berg, Ellen L.
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文献类型：
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作者：
Houck, Keith A.;Dix, David J.;Berg, Ellen L.
人类生物学的复杂性使得预测暴露在环境化学品中对健康的影响尤其具有挑战性。复杂的细胞系统，如生物多重活动图谱(BioMAP)主要的、人类的、基于细胞的疾病模型，利用细胞调控网络来检测和区分具有与人类毒性相关的广泛靶向机制和生物过程的化学物质。在这里，作者使用BioMAP人类细胞系统来表征与人体组织和炎症性疾病生物学相关的影响，这些影响是在暴露于环境保护局(EPA)ToxCast第一阶段库中的320种环境化学品后产生的。在8个BioMAP细胞系统中，在4个浓度下对ToxCast化学物质进行了检测，总共有87个检测终点，产生了超过100,000个数据点。在BioMAP数据库的背景下，ToxCast化合物可以根据它们对原代人类细胞类型造成明显细胞毒性的能力或根据与BioMAP参考化合物的活性图谱比较得出的毒性机制类别进行分类。基于这一BioMAP分析，确定了与线粒体功能障碍的诱导物、cAMP提升因子、微管蛋白功能的抑制物、内质网应激的诱导物或核因子kappaB途径抑制物相似的ToxCast化学物质。该数据集正在与其他ToxCast数据集相结合，用于在EPA开发预测性毒性模型。(生物分子筛选杂志2009：1054-1066)
The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, leverage cellular regulatory networks to detect and distinguish chemicals with a broad range of target mechanisms and biological processes relevant to human toxicity. Here the authors use the BioMAP human cell systems to characterize effects relevant to human tissue and inflammatory disease biology following exposure to the 320 environmental chemicals in the Environmental Protection Agency's (EPA's) ToxCast phase I library. The ToxCast chemicals were assayed at 4 concentrations in 8 BioMAP cell systems, with a total of 87 assay endpoints resulting in more than 100,000 data points. Within the context of the BioMAP database, ToxCast compounds could be classified based on their ability to cause overt cytotoxicity in primary human cell types or according to toxicity mechanism class derived from comparisons to activity profiles of BioMAP reference compounds. ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, CAMP elevators, inhibitors of tubulin function, inducers of endoplasmic reticulum stress, or NF kappa B pathway inhibitors were identified based on this BioMAP analysis. This data set is being combined with additional ToxCast data sets for development of predictive toxicity models at the EPA. (Journal of Biomolecular Screening 2009:1054-1066)