Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis

Determining the human relevance of structurally and functionally distinct non-genotoxic carcinogenic compounds that induce a diverse range of tissue-, gender-, strain- and species-specific tumours in animals remains a major challenge for toxicologists. Nevertheless, elucidating mechanisms of xenobiotic-induced tumours in animals can provide industry, environmental and regulatory scientists with valuable tools for cancer hazard identification and risk assessment. The discovery that aberrant epigenetic events frequently accompany genetic mutations in human cancers has stimulated efforts to deploy integrated epigenomic and transcriptomic profiling of xenobiotic-induced non-genotoxic carcinogenesis (NGC) in animal models, enabling enhanced mechanistic interpretation and novel early biomarker discovery. Recent advances in the mapping and functional characterization of mammalian tissue-specific epigenomes also provides new opportunities to characterize the cross-strain/-species chromatin architecture of non-genotoxic carcinogen effector genes and to predict their potential for modulation by xenobiotics in human tissue. Since xenobiotic-induced perturbations of gene regulation are intimately associated with the underlying DNA sequence, there is a need to integrate the impact of genotype on susceptibility to NGC. Furthermore, the potential association of xenobiotic target modulation with tumorigenic phenotypes can be assessed using genetic models and cancer genome resources. Finally, we discuss how epigenomic profiling may be used to critically assess the comparability and validity of cellular NGC models versus in vivo-derived tissue samples and some of key challenges associated with incorporating epigenetic mechanisms and biomarkers into cancer risk assessment.