NIEHS OPPE Factsheet #04 - July 2003
"Toxicogenomics" is an emerging discipline with significant promise for identifying gene-environment interactions that lead to complex diseases. It combines studies of genetics, genomic-scale mRNA expression, cell- and tissue-wide protein expression, lipids, carbohydrates, and small molecules, as well as bioinformatics, to understand how environmental toxicants interact with the genome to cause normal cells and tissues to become diseased.
Toxicogenomics can potentially improve our ability to use laboratory animals to predict effects of chemicals in people. Regulators often use data generated on the toxic effects of single chemicals in laboratory animals as a guide to predict the health risks of environmental exposures in people. This approach can be challenging because inbred laboratory animals are not representative of the variability found in human populations. Toxicogenomic data generated for multiple species can improve regulatory decision-making by allowing regulators to know how similar environmental response genes function in different species. These comparisons will be critical for (1) more accurately predicting toxicity in humans, (2) identifying conserved and functionally significant, genes and pathways of biological response leading to disease, and (3) providing important insights about how organisms respond and adapt to environmental exposures. Thus, using a "comparative genomics" approach focused on environmental response genes across different species will greatly enhance our understanding about the complex interaction between genes, environment, and human health.
The reality, though, is that toxicogenomic databases cannot currently support these research and regulatory goals. One of the greatest challenges for comparative toxicogenomics is the integration of the vast amount of genomic information being generated for a variety of model organisms. At present, there are several disparate but complementary databases on genomic sequences. Most of these databases provide data on gene and genome sequences for individual animal species. These databases do not provide a means to link the genome data to specific environmental chemicals or to toxicological and biological endpoints. They also do not enable researchers to compare information about potentially similar genes and biological responses across multiple species.
Integrating the large number of disparate data sets is the goal of the Comparative Toxicogenomics Database (CTD). The CTD was developed through a collaboration of five NIEHS-funded Marine and Freshwater Biomedical Sciences Centers. These centers include: Mount Desert Island Biological Laboratory, Oregon State University, University of Wisconsin-Milwaukee, University of Miami and the Jackson Laboratory. The goal of the CTD is to develop a comparative database that links sequence information for genes that are relevant to toxicology to information about gene expression, toxicology and biological processes. The primary focus of the CTD is on marine and aquatic organisms as model systems for human diseases. The initial focus is also on genes that have been identified through the NIEHS' Environmental Genome Project (EGP) as important for toxicology in these model systems. However, the database will eventually merge all gene sequence information generated on all vertebrates and invertebrates, including aquatic organisms, worms, flies, rodents, and people. The CTD provides information about gene curation and annotation (gene synonyms, sets and functions) and links between gene sequence and toxicity data published in the scientific literature. These aspects of the database represent an important advancement for comparative toxicogenomics. Such information will include all of the synonyms by which a gene is known in different organisms, the toxicant responses identified for specific genes in different species, and a platform that promotes comparisons of gene sequences and toxicant activity among diverse organisms. This data structure will provide comprehensive information about the mechanism of action of toxicants. Understanding these mechanisms will allow more informed assessment of human risk by extrapolating toxicity data from animal models to people and will provide a mechanism by which members of the research community can share their data and promote fruitful avenues for future toxicological research.
At present, the Comparative Toxicogenomics Database is the only fully curated, publicly available database of its kind in the world. However, it serves as a prototype database and data resource for more comprehensive efforts ongoing at the NIEHS. By building on the data infrastructure being developed through the CTD and other databases, NIEHS scientists are developing the sequence-driven and context-documents Chemical Effects in Biological Systems (CEBS) knowledge base. CEBS is planned as a public toxicogenomics knowledge base that combines and integrates scientific data from a multitude of public domain data sources. These data sources include studies of genetic polymorphisms, gene expression and proteomics, metabolism and toxicology. The data sources will be linked at the level of the gene sequence. Thus, CEBS is being designed with the long-term goal of meeting the information needs of systems toxicology by providing a public data resource for toxicogenomics. The final payoff for investing in CTD and CEBS will be more rational environmental health policy and an improved understanding of gene-environment contributions to the major causes of human death and disease.
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NIEHS OPPE Factsheet #04 - July 2003
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