ABSTRACT
According to the latest calculations, there are about 20,000 genes in the mammalian genome (Carninci and Hayashizaki 2007; Claverie 2005) and, simply stated, up to 40% of them (~8000) may be actively transcribed (expressed as indicated by production of gene-specic messenger or mRNAs) at a baseline in normal tissues (Malarkey et al. 2005). This number is signicantly lower than earlier estimates of 100,000 genes in the genome and reects the complex efciency of the genome to make multiple proteins from a single gene (Carninci and Hayashizaki 2007). Under environmental stressors or in disease states, there can be enhancement or suppression of baseline genes in addition to the expression of inactive genes. The study of the array of up-and downregulated genes under various conditions and disease states is the basis of the eld called genomics. Genomics is also called transcriptomics because it refers to the process of transcription, that is, production of mRNA copies of coding DNA. Generally, but not always, the mRNA is spliced and translated into specic proteins. Proteomics refers to the study of translation and protein modication. Gene expression can be inuenced by epigenetic events, or alterations in expression of genes without modication of the underlying genetic sequence, through such processes as methylation, microRNA, or histone deacetylation, whereby gene expression is suppressed or inhibited (Holliday
7.1 Introduction .......................................................................................................................... 175 7.1.1 -Omics: The Basics ................................................................................................... 175 7.1.2 -Omics Revolution .................................................................................................... 176
7.2 Basic Array Technologies ..................................................................................................... 177 7.3 Toxicologic Pathologist’s Role in Toxicogenomics ............................................................... 178 7.4 Pathway and Network Analyses ........................................................................................... 181 7.5 Applications of Toxicogenomics ........................................................................................... 182
7.5.1 Phenotypic Anchoring .............................................................................................. 182 7.5.2 Predictive versus Mechanistic Toxicogenomics ....................................................... 183 7.5.3 Prediction of Carcinogens Using Toxicogenomics ................................................... 185
7.6 Genotoxic versus Nongenotoxic ........................................................................................... 185 7.7 Toxicogenomic Proling of Hepatotoxicity .......................................................................... 188 7.8 Toxicogenomic Proling of Nephrotoxicity ......................................................................... 194 7.9 Toxicogenomic Proling of Cardiotoxicity .......................................................................... 197 7.10 Toxicogenomic Databases .................................................................................................... 199 7.11 Summary and Conclusions ...................................................................................................200 Glossary ......................................................................................................................................... 201 References ...................................................................................................................................... 201
1994). Hypermethylation, for example, inhibits gene expression through methylation of CpG islands in DNA coding sequences. The large-scale investigation of global gene methylation is also called methylomics. MicroRNAs have more recently been identied to exert control of gene expression (Wang et al. 2009). The study of metabolites in body uids is called metabolomics and the interaction of all the -omics is called interactomics. The various and increasing number of “-omics” elds are outside the scope of this chapter; instead, the focus of this chapter will be on the application of toxicogenomics.
