Patterns With Promise for Toxicogenomics

A study in this 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; these genes play roles in phase I and phase II metabolism, DNA repair, stress response, cell signaling and housekeeping. Led by Alan Buckpittat the University of California, Davis, the researchers analyzed the transcriptional profile of mice exposed to a range of doses of cadmium chloride, benzo(a)pyrene or trichloroethylene, three compounds that fall into distinct chemical classes. The authors chose a small subset of mouse genes and a small number of environmental contaminants because they consider this study to be a "proof of principle" experiment.

Buckpitt's results clearly show that a distinct set of genes are induced and/or repressed in mice exposed to these three agents. The authors provide proof that "these three environmental contaminants....elicit unique patterns of gene expression over the doses tested in an in vivo model." A statistically significant change in expression was observed for 16 of the 148 genes in the DNA microarray. These 16 genes are metallothionein I, metallothionein II, heat shock proteins 108, 25 and 86, GFIP, chop10, c-jun, jun-b, cyp1a1, cyp1a2, cyp2a, cyp2f2, cyp3a11, methyl transferase 111, and acetyltransferase 96. Several differences were noted in the specific gene expression pattern in this study and other earlier studies. Future work will determine if these differences are due todifferent experimental systems (i.e., in vivo vs. in vitro) or tissue- or dose-specificity.

In addition to this work using an in vivo mouse model, several comprehensive DNA microarray studies have been carried out based on the complete genome sequenceof Saccharomyces cerevisiae. Stephen Friend and colleagues at Rosetta Inpharmatics studied expression of 386 yeast genes in 46 different experimental conditions (Science 287:873-880). Leona Samson and colleagues at Harvard School of Public Health examined genome-wide response to four mutagenic/genotoxic agents: methyl methanesulfonate, tert?butylhydroperoxide, 4-nitroquinoline n-oxide and g-irradiation (Mol. Cell Biol. 20:8157-8167). These and other studies establish 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 Buckpitt 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.