Chapter 2: Genomic Biomarkers in Cell-based Drug Screening
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Published:16 Jun 2016
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Special Collection: 2016 ebook collectionSeries: Issues in Toxicology
H. Li, in Toxicogenomics in Predictive Carcinogenicity, ed. R. S. Thomas and M. D. Waters, The Royal Society of Chemistry, 2016, ch. 2, pp. 39-75.
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The development of in vitro molecular biomarkers to accurately predict toxicological effects has become a priority to advance testing strategies for human health risk assessment. The application of in vitro transcriptomic biomarkers promises increased throughput as well as a reduction in animal use. However, the fact that toxic agents may have pleiotropic effects and the lack of established guidelines for identifying the genomic biomarker make it difficult to compare transcriptome profiles across agents and studies. In this chapter we use genotoxicity as an example to elucidate how the genomic biomarker facilitates toxicity screening. Characteristic genotoxic stress response is discussed and an innovative cell-based biomarker application pipeline incorporating a dose optimization protocol is introduced. Based on this new experimental protocol and using the nearest shrunken centroids method a biomarker comprised of a panel of 65 genes has been identified, which could accurately classify toxicants as genotoxic or non-genotoxic. To validate the 65-gene panel as a genomic biomarker of genotoxicity, gene expression profiles of additional well-characterized model agents were analyzed and the case study demonstrated the practical application of this genomic biomarker-based approach in genotoxicity risk assessment.