Abstract
There is a high need to improve the assessment of, especially non-genotoxic, carcinogenic features of chemicals. We therefore explored a toxicogenomics-based approach using genome-wide microRNA and mRNA expression profiles upon short-term exposure in mice. For this, wild-type mice were exposed for seven days to three different classes of chemicals, i.e., four genotoxic carcinogens (GTXC), seven non-genotoxic carcinogens (NGTXC), and five toxic non-carcinogens. Hepatic expression patterns of mRNA and microRNA transcripts were determined after exposure and used to assess the discriminative power of the in vivo transcriptome for GTXC and NGTXC. A final classifier set, discriminative for GTXC and NGTXC, was generated from the transcriptomic data using a tiered approach. This appeared to be a valid approach, since the predictive power of the final classifier set in three different classifier algorithms was very high for the original training set of chemicals. Subsequent validation in an additional set of chemicals revealed that the predictive power for GTXC remained high, in contrast to NGTXC, which appeared to be more troublesome. Our study demonstrated that the in vivo microRNA-ome has less discriminative power to correctly identify (non-)genotoxic carcinogen classes. The results generally indicate that single mRNA transcripts do have the potential to be applied in risk assessment, but that additional (genomic) strategies are necessary to correctly predict the non-genotoxic carcinogenic potential of a chemical.
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Acknowledgments
We thank the Animal Facilities of the National Institute for Public Health and the Environment for their skillful (bio-)technical support. We thank Novartis Pharma AG for providing cyclosporine A. The work presented here was in part financially supported by the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO) Grant Number 050-060-510, and the Dutch Technology Foundation (STW) Grant Number STW-LGC.06935.
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The authors declare there is no conflict of interest.
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Joost P. M. Melis and Kasper W. J. Derks have contributed equally to this work.
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Melis, J.P.M., Derks, K.W.J., Pronk, T.E. et al. In vivo murine hepatic microRNA and mRNA expression signatures predicting the (non-)genotoxic carcinogenic potential of chemicals. Arch Toxicol 88, 1023–1034 (2014). https://doi.org/10.1007/s00204-013-1189-z
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DOI: https://doi.org/10.1007/s00204-013-1189-z