A Toxic Form of Expression: Different Agents Affect Different Genes.

Toxicogenomics is a topic of great current interest. A quick scan of the contents of any scientific journal is likely to turn up several articles on the closely related topics of expression profiling, proteomics, toxicogenomics, and bioinformatics. Toxicologists are intensely interested in expression profiling--monitoring and comparing the expression of hundreds or thousands of genes simultaneously--because this approach, once fully developed and validated, could provide an alternative to traditional toxicologic animal bioassays that would be much faster, less costly, more sensitive and informative, and nonanimal-based.

A study in this month's issue examines gene expression in mouse liver using a DNA microarray that includes 148 mouse genes presumed to play a role in response to environmental exposure [EHP 109:71-74]. These genes play roles in phase I and phase II metabolism, DNA repair, stress response, cell signaling, and housekeeping. Led by Matthew Bartosiewicz, a graduate student in the molecular biology laboratory of Alan Buckpitt at the University of California at Davis, a team of researchers analyzed the transcriptional profile of mice exposed to a range of doses of cadmium chloride, benzo(a)pyrene, or trichloroethylene, three environmental/occupational contaminants that fall into distinct chemical classes. The goal was to test the hypothesis that chemicals of different classes have distinct profiles to determine how useful the technique might be in future toxicology testing. The authors chose a small subset of mouse genes and a small number of compounds because they consider this study to be a "proof of principle" experiment.

The group's results clearly show that a distinct set of genes is induced and/or repressed in mice exposed to these three agents. A statistically significant change in expression was observed for 16 of the 148 genes in the DNA microarray. The authors believe their findings provide proof that "these three environmental contaminants ... elicit unique patterns of gene expression over the doses tested in an in vivo model."

This in vivo work confirms several earlier, comprehensive DNA microarray studies that have been carried out based on the complete genome sequence of Saccharomyces cerevisiae, which have established that DNA microarray technology can provide quantitative information on changes in gene expression due to altered cellular environment, disease, and/or exposure to stress. The present study by Bartosiewicz and colleagues is a promising demonstration that environmentally important agents can be monitored using DNA microarray technology in an in vivo mammalian system. Due to these efforts, the groundwork is steadily being laid for future use of expression profiling in toxicology testing.

Although the patterns of gene induction in this study largely agree with those found in earlier studies, there were some differences for genes that had previously been up-regulated in association with benzo(a)pyrene. Future work will determine if these differences are due to differences between in vivo and in vitro experimental systems, or tissue or dose specificity.