Gene expression profiling in primary mouse hepatocytes discriminates true from false-positive genotoxic compounds

Mutagenesis
Karen MathijsJoost H M van Delft

Abstract

Well-established in vitro methods for testing the genotoxic potency of chemicals--such as the Ames/Salmonella test, the mouse lymphoma assay, the micronucleus test and the chromosomal aberration test--show a high false-positive rate for predicting in vivo genotoxicity and carcinogenicity. Thus, there is a need for more reliable in vitro assays. We investigated whether gene expression profiling in metabolically competent primary mouse hepatocytes is capable of discriminating true genotoxic (GTX) compounds from false-positive genotoxic (FP-GTX) compounds. Sandwich-cultured primary hepatocytes from male C57Bl6 mice were treated for 24 and 48 h with five true GTX and five FP-GTX compounds. Whole genome gene expression modifications were analysed by means of Affymetrix mouse genome 430 2.0 microarrays. Filtered genes were used for hierarchical clustering and class prediction methods. Classifiers were generated by prediction analysis of microarray using a leave-one-compound-out method and selecting the genes that were common to the 10 training sets. For the training compounds, all but one were correctly classified. Validation of the classification model with five new compounds resulted in a 100% correct classification at 24 h and 80%...Continue Reading

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Citations

Jun 20, 2012·Archives of Toxicology·Mirjam M SchaapMirjam Luijten
May 3, 2011·Archives of Toxicology·Sarah AdlerJosé-Manuel Zaldivar
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Sep 25, 2017·Environmental Health Perspectives·Danqi ChenChunyuan Jin

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