Toxicogenomics Approaches to Address Toxicity and Carcinogenicity in the Liver

Abstract

Toxicogenomic technologies query the genome, transcriptome, proteome, and the epigenome in a variety of toxicological conditions. Due to practical considerations related to the dynamic range of the assays, sensitivity, cost, and technological limitations, transcriptomic approaches are predominantly used in toxicogenomics. Toxicogenomics is being used to understand the mechanisms of toxicity and carcinogenicity, evaluate the translational relevance of toxicological responses from in vivo and in vitro models, and identify predictive biomarkers of disease and exposure. In this session, a brief overview of various transcriptomic technologies and practical considerations related to experimental design was provided. The advantages of gene network analyses to define mechanisms were also discussed. An assessment of the utility of toxicogenomic technologies in the environmental and pharmaceutical space showed that these technologies are being increasingly used to gain mechanistic insights and determining the translational relevance of adverse findings. Within the environmental toxicology area, there is a broader regulatory consideration of benchmark doses derived from toxicogenomics data. In contrast, these approaches are mainly used for internal decision-making in pharmaceutical development. Finally, the development and application of toxicogenomic signatures for prediction of apical endpoints of regulatory concern continues to be area of intense research.

Keywords: carcinogenicity; liver; mechanisms; toxicity; toxicogenomics.

Figure 1

Variability of gene expression profiles compared to serum ALT values. Eight male rats were dosed daily for 3 days with a slightly toxic dose of a tool hepatoxic compound, and 3 male rats were dosed with the vehicle. On the right column are the serum ALT values 24 hours after the last dose when rats were sacrificed. Gene expression profiles were generated using the rat Affymetrix microarray for all rats. Shown here are the genes that were altered at a p value less than 0.01 and with at least a 2-fold change compared to the three control animal profiles pooled in silico. Note that overall, the gene expression profiles for the rats exposed to the hepatotoxicant show little variability, at least comparable if not better than the serum ALT values. Early in lead optimization efforts, this limited variability enables the use of a low number of animals and hence a much lower quantity of test article, which is clear advantage at a stage where compound amount can be limited, but also from a 3R perspective.