FORUM Concise Review: Gene Expression Applied to Toxicology

Toxicogenomics and toxicogenetics are the application of genomics and genetics, respectively, to toxicology. The major focus of toxicogenetics is the study of differential gene expression induced as an adaptation or “change-of-plans” response to chemical or environmental stress. This review attempts to summarize the status of toxicogenetics. Some of the essential issues and questions surrounding toxicogenetics that we have attempted to address in this review are as follows: Why study gene expression in the context of toxicology? What are the goals of toxicogenetics? What is the relationship between the number of traditional toxicological endpoints and the number of possible gene-expression patterns? Basic characteristics of “stress genes” or “tox” genes. Interpretation of gene expression data. Inductive vs. deductive arrays. Challenges and next steps. Because of space constraints, it is not possible to cover the subject in both breadth and depth. While striving for some compromise, we are mindful of the risk that neither has been achieved. It is hoped, nevertheless, that the reader will find something of value herein. Why Study Gene Expression in the Context of Toxicology? The fundamental assumption of toxicogenetics is that there are no toxicologically relevant outcomes in vitro or in vivo, with the possible exception of rapid necrosis, that do not require differential gene expression. As used in this review, differential gene expression includes differential transcription and translation, as well as message stabilization. It also encompasses both up- and down-expression of genes. Toxicologically relevant outcomes include all traditional endpoints normally considered of importance in analysis of the adverse effects caused by chemicals, both in vivo and in vitro. It is also likely that as-yet-undiscovered manifestations of chemically induced toxicity require changes in gene expression. While multiplex gene expression data are available for only a few dozen compounds, that data and theoretical considerations also suggest that most toxicologically-relevant outcomes require not only differential gene expression, but also differential expression of multiple genes. The short answer to the above question is that by studying patterns of gene expression, we can learn a great deal about the fundamental mechanisms of chemical toxicity. In addition, measurement of gene expression may allow us to identify threshold concentrations below which there is little health risk.