dioxin and related chemicals as well as the report of the International Agency for Cancer Research on the human carcinogenicity of benzo(a)pyrene (IARC 1987) exemplify the usefulness of mechanism-based information in risk assessment. In sharp contrast to the chemical industry, the pharmaceutical industry routinely uses mechanisms and molecular level understanding to identify off-target biologic responses to potential new compounds and products already on the market. In fact, these data are used in new drug applications for regulatory approval by the Food and Drug Administration. In both settings, mechanistic studies have greatly facilitated informed decision making and more detailed understanding of critical issues.
Toxicogenomic studies offer the opportunity to evaluate molecular mechanisms of toxic action and the degree of conservation of biologic response pathways across species that are responsible for toxicity. When applied to the study of large classes of chemicals or drugs, toxicogenomic information can be used to globally define modes or mechanisms of toxic action. The application of toxicogenomics to the study of toxicity mechanisms rests on the premise that chemical or physical injury is mediated by, or reflected in, changes at the mRNA, protein, or metabolite level. Abundant evidence supports this concept that toxicity coincides with changes in mRNAs, proteins, and metabolites. As such, these changes under defined conditions of cellular location, time, and biologic context can provide meaningful information about biologic responses to toxic insult. Thus, toxicogenomic studies offer a new dimension in environmental exposure assessment, drug and chemical screening, and understanding of human and animal variability in response to drugs and chemicals.
This chapter provides examples of the application of toxicogenomic analyses for exploring toxicity mechanisms of environmental chemicals and pharmaceuticals. Because transcriptome profiling technologies are technically more mature than methods for proteomics or metabonomics, the discussion focuses primarily on transcriptomics, with complementary insights derived from proteomics and metabonomics. The limitations of the various technologies and a needs assessment are also presented.
Investigators have exploited transcriptome profiles to understand mechanisms of environmental chemical or drug toxicity. Generally, the experimental approaches used can be categorized in three broad approaches (Box 7-1), which are discussed later in this chapter: the contextual approach, the exploratory approach, and the network building approach.
Transcriptome profiling experiments designed to evaluate toxicity provide a “snapshot” of global gene activity as measured by steady-state levels of mRNA at a precise point in time during the course of the toxic response. Genetic and epigenetic mechanisms that orchestrate the recruitment of RNA polymerase