The National Center for Toxicogenomics: using new technologies to inform mechanistic toxicology.

VOLUME 110 | NUMBER 1 | January 2002 • Environmental Health Perspectives The science of toxicology has evolved from the empirical codification of dose-related effects to studies directed toward understanding the mechanisms by which individual agents cause their effects in humans. Due to technical limitations, this evolution has been relatively slow, being accomplished one chemical or one effect at a time. To prospectively use the understanding gained on the mode of action of a single chemical, it is also necessary to know about structurally and functionally related chemicals and their timeand dose-dependent biological effects. In addition to chemicals and drugs, there are a plethora of environmental factors and stressors, such as ultraviolet and ionizing radiation, biological agents, and dietary and lifestyle components, that can contribute to the development of disease. The effects of all of these agents must be characterized to a progressively greater depth for us to understand the biochemical and genetic complexity of the cells in which adverse effects are manifested. In this view, toxicology will progressively develop from predominantly individual chemical studies into a knowledge-based science in which experimental data are compiled and computational and informatics tools will play a significant role in deriving a new understanding of toxicant-related disease (1). The application of gene expression technology to understand the actions of chemicals and other environmental stressors on biological systems has been catalyzed by the rapid development of genomebased technology (2–4). The capacity to array large numbers of individual gene fragments on small matrices that can be hybridized to mRNA or cDNA has made it possible to synchronously assess the variety of effects that specific chemicals can cause, both good and bad. These technologic advances have led to the development of the field of toxicogenomics, which proposes to apply both mRNA and protein expression technologies to study chemical effects in biological systems (5–11). In recognition of the unique scientific opportunities afforded by this approach, the National Institute of Environmental Health Sciences (NIEHS) has created the National Center for Toxicogenomics (NCT). This center’s mission is to promote the evolution and coordinated use of gene expression technologies and to apply them to the assessment of toxicologic effects in humans. The primary goal is to provide a worldwide reference system of genome-wide gene expression data and to develop a knowledge base of chemical effects in biological systems. Such a knowledge base will also, as a secondary goal, provide a profound understanding of the mechanisms by which stressor-induced injury occurs. The NCT was formally established in September 2000 and is working to implement a strategy through which its mission can be achieved. There is implicit recognition that the goals are long-range and that substantial time and effort will be required to develop a truly informative knowledge base. Due to the magnitude and complexity of the science underlying these goals, a central theme of the NCT is the formation of national and international consortia of universities, other federal research and regulatory agencies, and private sector organizations. Some researchers (10,12) have expressed concern that the capacity to rapidly obtain large amounts of data on chemical effects using these technologies could result in inappropriate decisions about the potential for chemical-induced adverse effects. However, collective efforts such as those proposed in the NCT partnerships will do much to help develop scientific consensus on the appropriate uses of gene expression data. Practical matters will dominate in the early stages of the NCT. Importantly, development of a reference database will require some effort at achieving a consensus on content and data quality standards. In addition, it is highly desirable that the data be preserved in a primary form so as to permit reanalysis as bioinformatics tools evolve and improve. We must approach all of these efforts in an incremental fashion, recognizing that in the face of rapid technologic change, it is impossible to anticipate all of the opportunities and problems that can and will develop. Within this incremental approach several steps can be clearly defined. The first step is to test the hypothesis that signature profiles of individual chemicals, drugs, and other stressors can be defined. It is also necessary to test the hypothesis that specific toxicities will carry signature profiles and that these profiles can be recognized within certain dose-and-time parameters. The NCT is conducting a series of “proof-of-principle” experiments that are designed to establish signature profiles and to link the patterns of altered gene expression to specific parameters of welldefined, conventional indices of toxicity. This “phenotypic anchoring” of gene expression data to conventional toxic effects is necessary to clearly demarcate pharmacologic or incidental effects from those changes either associated with or causal of adverse effects. A learning set of data on both pharmacologic and toxic gene expression profiles would then allow for distinguishing and predicting adverse effects for other well-defined compounds that could be tested under code. These data will help to establish the use of empirical gene expression profiles for toxicologic characterization, particularly chronic toxicity, which has been and will continue to be a focus of the NIEHS. Recent studies using a relatively small learning set (13–15) and RNAs that are tested in blind studies have shown that it is possible to identify signature expressed gene patterns (13). This is an extremely important advance for the field and serves as the first major validation of the hypothesis that signature gene arrays can be defined and reproduced. Because these studies were conducted on acutely exposed animals, the array patterns appear to be representative of the pharmacologic activity of the chemicals. One group within the NCT The National Center for Toxicogenomics: Using New Technologies to Inform Mechanistic Toxicology PERSPECTIVES Editorial