A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens

Arch Toxicol. 2015 Dec;89(12):2413-27. doi: 10.1007/s00204-014-1368-6. Epub 2014 Oct 2.


Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

Keywords: Comparison approach; Gene expression profiles; Mode of action; Mouse embryonic stem cells; Non-genotoxic carcinogens; Primary mouse hepatocytes; Safety assessment of chemicals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / toxicity*
  • Down-Regulation / drug effects
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / pathology
  • Gene Expression Profiling
  • Hepatocytes / drug effects*
  • Hepatocytes / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutagens / toxicity
  • Toxicogenetics / methods*
  • Up-Regulation / drug effects


  • Carcinogens
  • Mutagens