Application of toxicogenomics to genetic toxicology risk assessment.
Based on the assumption that compounds having similar toxic modes of action induce specific gene expression changes, the toxicity of unknown compounds can be predicted after comparison of their molecular fingerprints with those obtained with compounds of known toxicity. These predictive models will therefore rely on the characterization of marker genes. Toxicogenomics (TGX) also provides mechanistic insight into the mode of toxicity, and can therefore be used as an adjunct to the standard battery of genotoxicity tests. Promising results, highlighting the ability of TGX to differentiate genotoxic from non-genotoxic carcinogens, as well as DNA-reactive from non-DNA reactive genotoxins, have been reported. Additional data suggested the possibility of ranking genotoxins according to the nature of their interactions with DNA. This new approach could contribute to the improvement of risk assessment. TGX could be applied as a follow-up testing strategy in case of positive in vitro genotoxicity findings, and could contribute to improve our ability to identify the molecular mechanism of action and to possibly better assess dose-response curves. TGX has been found to be less sensitive than the standard genotoxicity end-points, probably because it measures the whole cell population response, when compared with standard tests designed to detect rare events in a small number of cells. Further validation will be needed (1) to better link the profiles obtained with TGX to the established genotoxicity end-points, (2) to improve the gene annotation tools, and (3) to standardise study design and data analysis and to better evaluate the impact of variability between platforms and bioinformatics approaches.
Thybaud
Véronique
V
Drug Safety Evaluation, Sanofi Aventis R&D, Vitry sur Seine, France. veronique.thybaud@sanofi-aventis.com
Le Fevre
Anne-Céline
AC
Boitier
Eric
E
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008957:Models, Genetic; D009152:Mutagenicity Tests / Q000379:methods / Q000592:standards; D009153:Mutagens / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D018570:Risk Assessment / Q000379:methods / Q000592:standards; D043922:Toxicogenetics / Q000379:methods* / Q000592:standards*
D002273:Carcinogens; D009153:Mutagens