Application of transcript profiling to mechanism-based toxicology

Technologies stemming from recent advances in the genomic sciences are set to revolutionise toxicology. Among these technologies is transcript profiling, which permits the simultaneous measurement of the expression levels of thousands of different genes. The application of transcript profiling to toxicology has been termed toxicogenomics and promises to accelerate identification of the molecular mechanisms through which xenobiotics induce adverse health effects. One of the main obstacles to the successful application of this technology is the lack of information on the relationship between the regulation of specific genes and the development of toxicity. In this article, we describe some of the approaches we are taking in our own laboratory to understand this relationship. Transgenic ‘knock-out’ mice and cell lines in which components of toxicant-signalling pathways have been modified or deleted are used to facilitate the identification of genes directly related to mechanisms of toxicity. In addition, analysis of gene regulatory regions can reveal the biological pathways that regulate transcriptional responses to toxicants, leading to a better understanding of molecular mechanisms of toxicity.