Chapter 4: In vivo Signatures of Genotoxic and Non-genotoxic Chemicals

This chapter reviews the findings from a broad array of in vivo genomic studies with the goal of identifying a general signature of genotoxicity (GSG) that is indicative of exposure to genotoxic agents (i.e. agents that are active in either the bacterial mutagenesis and/or the in vivo micronucleus test). While the GSG has largely emerged from systematic studies of rat and mouse liver, its response is evident across a broad collection of genotoxic treatments that cover a variety of tissues and species. Pathway-based characterization of the GSG indicates that it is enriched with genes that are regulated by p53. In addition to the GSG, another pan-tissue signature related to bone marrow suppression (a common effect of genotoxic agent exposure) is reviewed. Overall, these signatures are quite effective in identifying genotoxic agents; however, there are situations where false positive findings can occur, for example when necrotizing doses of non-genotoxic soft electrophiles (e.g. thioacetamide) are used. For this reason specific suggestions for best practices for generating for use in the creation and application of in vivo genomic signatures are reviewed.