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

Abstract

Determining the human relevance of structurally and functionally distinct non-genotoxic carcinogenic compounds that induce a diverse range of tissue-, gender-, strain-and speciesspecific tumors in animals remains a major challenge for toxicologists. Nevertheless, elucidating mechanisms of xenobiotic-induced tumors 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 crossstrain/-species chromatin architecture of non-genotoxic carcinogen effector genes and to predict their potential for modulation by xenobiotics in human tissue. Since xenobioticinduced 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.

Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice

“…Given that HCC are driven by various known environmental factors, understanding genetic and epigenetic alterations would help better understand the underlying molecular mechanism of carcinogenesis of these tumors. The application of integrated epigenomic and transcriptomic profiling (Terranova et al 2017).…”

Effects of Trichloroethylene on the Expression of Long Intergenic Noncoding RNAs in B6C3F1 Mouse Liver

“…12 This kind of species-or organ-specific carcinogenicity is one of the characteristics of epigenetic carcinogens. 13 Epigenetic modifications such as DNA methylation, histone modifications, microRNA (miRNA), and long intragenic noncoding RNA (LincRNA) are suggested to be essential to liver cancer initiation, promotion, and progression. 14,15 Long intergenic noncoding RNAs (LincRNAs) are a group of noncoding RNA molecules localized between protein-coding loci, with length ranges from 200 nucleotides to 100 kilobases.…”

“…Indeed, through animal experiments, there is consistent evidence that TCE induced liver cancer in mice and kidney cancer in rats . This kind of species- or organ-specific carcinogenicity is one of the characteristics of epigenetic carcinogens …”

Defining Baseline Epigenetic Landscapes in the Rat Liver

“…Epigenetic responses had also been implicated in hepatotoxic responses to xenobiotics [5–7]. Unlike genetic perturbations, changes to the epigenetic landscape following toxicological insult are potentially reversible.…”