A central tenet of toxicology is that with the possible exception of acute cell necrosis, every toxic exposure leads to an alteration in the pattern of gene expression. This altered pattern of gene expression reflects the cell?s attempt to cope with the toxic insult, and can range from induction of xenobiotic metabolism to the extreme of cell suicide or apoptosis. While numerous studies have looked at changes in the expression of a limited number of genes thought to play a role in these adaptive responses, the power of array technology is the ability to obtain a comprehensive survey of thousands of genes simultaneously. This global analysis of gene expression affords researchers the ability to discern specific patterns or signatures of expression that are associated with particular classes of toxicants. These signatures are likely to include classes of genes not previously implicated in response to specific toxic insult. As such the applications of array technologies to toxicology will undoubtedly enhance our understanding of the cellular response to toxicants, which should by inference also provide insight into the mechanism of drug responses, toxicity, development effects and induction of disease. The unifying theme of the present proposal is that the comparison of gene expression profiles induced by stressors or toxicants in cells that are differentially sensitive to their effects will be particularly useful in dissecting the biochemical pathways underlying a toxic response. The investigators have assembled a team experts in the areas of biotransformations, neurodevelopmental toxicology, and carcinogenesis with the common goal of using DNA microarray technologies to compare gene expression profiles among mouse and rat, and human cells that are differentially sensitive to a variety of environmental agents. A series of four projects and a Toxicology Research Core Project, all of which make use of genetically defined rats or mice, transgenic and knockout mice and primary human and rodent cell cultures are proposed. The projects will be supported by an Administrative Core and essential three facility cores. The DNA Microarray Facility Core will provide project researchers access to the state-of-the-art facility established at the Fred Hutchinson Cancer Research Center by Dr. Zarbl. The Tissue Acquisition Core will project researchers access the Transgenic/Knockout Mice facility at the University of Washington, providing researchers access to genetically defined mice and their tissues. Recognizing the need to look at individual cell types comprising organs, the investigators also included within this Core access to cell enrichment technologies. The Tissue Acquisition Core will provide researchers access to high speed cell sorting and laser capture microdissection capabilities. The final facilities core will provide bioinformatic and biostatistics support to the project researchers. These latter will be required for coordinating the acquisition, processing, storing and analyzing the large volumes of data that will be generated by the project researchers. Each of the Cores will also interact with other Consortium members and the central contractor through the Toxicology Research Core Project to perform cross species and cross platform comparisons and to develop standards for data standardization. The latter will be essential for the generation of a public database for data generated by all members of the Consortium.
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