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DOI | 10.1093/toxsci/kfx021 |
Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment | |
Dean, Jeffry L.1; Zhao, Q. Jay1; Lambert, Jason C.1; Hawkins, Belinda S.1; Thomas, Russell S.2; Wesselkamper, Scott C.1 | |
发表日期 | 2017-05-01 |
ISSN | 1096-6080 |
卷号 | 157期号:1页码:85-99 |
英文摘要 | The rate of new chemical development in commerce combined with a paucity of toxicity data for legacy chemicals presents a unique challenge for human health risk assessment. There is a clear need to develop new technologies and incorporate novel data streams to more efficiently inform derivation of toxicity values. One avenue of exploitation lies in the field of transcriptomics and the application of gene expression analysis to characterize biological responses to chemical exposures. In this context, gene set enrichment analysis (GSEA) was employed to evaluate tissue-specific, dose-response gene expression data generated following exposure to multiple chemicals for various durations. Patterns of transcriptional enrichment were evident across time and with increasing dose, and coordinated enrichment plausibly linked to the etiology of the biological responses was observed. GSEA was able to capture both transient and sustained transcriptional enrichment events facilitating differentiation between adaptive versus longer term molecular responses. When combined with benchmark dose (BMD) modeling of gene expression data from key drivers of biological enrichment, GSEA facilitated characterization of dose ranges required for enrichment of biologically relevant molecular signaling pathways, and promoted comparison of the activation dose ranges required for individual pathways. Median transcriptional BMD values were calculated for the most sensitive enriched pathway as well as the overall median BMD value for key gene members of significantly enriched pathways, and both were observed to be good estimates of the most sensitive apical endpoint BMD value. Together, these efforts support the application of GSEA to qualitative and quantitative human health risk assessment. |
英文关键词 | human health risk assessment;gene expression;enrichment;transcriptomics;toxicogenomics;GSEA |
语种 | 英语 |
WOS记录号 | WOS:000402861100010 |
来源期刊 | TOXICOLOGICAL SCIENCES
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来源机构 | 美国环保署 |
文献类型 | 期刊论文 |
条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/62157 |
作者单位 | 1.US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA; 2.US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA |
推荐引用方式 GB/T 7714 | Dean, Jeffry L.,Zhao, Q. Jay,Lambert, Jason C.,et al. Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment[J]. 美国环保署,2017,157(1):85-99. |
APA | Dean, Jeffry L.,Zhao, Q. Jay,Lambert, Jason C.,Hawkins, Belinda S.,Thomas, Russell S.,&Wesselkamper, Scott C..(2017).Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment.TOXICOLOGICAL SCIENCES,157(1),85-99. |
MLA | Dean, Jeffry L.,et al."Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment".TOXICOLOGICAL SCIENCES 157.1(2017):85-99. |
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