Application of DNA microarrays for predicting toxicity and evaluating cross-species extrapolation

Summary

The application of DNA microarray technology to the field toxicology has increased significantly. In most cases, the research has monitored global changes in gene expression in order to provide insight into the cellular mechanisms of toxicity. Although assessing global gene expression changes may prove to be important when characterizing the action of a particular chemical, it is not necessarily predictive of the toxicological behavior within an organism or across species. As a first step for developing predictive toxicological models within a species, we developed a statistical model to classify 24 model treatments that fall into five well-studied toxicological categories based on gene expression. Using all the gene expression measurements resulted in relatively poor predictive accuracy. However, focusing on a diagnostic subset of genes greatly increased the predictive accuracy. For evaluating the toxicological behavior across species, a set of orthologous microarrays were developed that allowed a direct comparison of gene expression changes in both organisms. To construct these microarrays, a genome wide comparison of available human and mouse sequence was performed to identify putative orthologous genes. A subset of the orthologous genes were spotted on tandem microarrays (one human and one mouse) and used to evaluate conservation of expression patterns between organisms. The use of predictive statistical models and cross-genome comparisons in chemically induced gene expression are the next logical advancements in the field of toxicogenomics and their application has the potential to be extremely valuable in regulatory decisions and the risk assessment process.