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

Transcriptomic profiles of muscle, heart, and spleen in reaction to circadian heat stress in Ethiopian highland and lowland male chicken

Temperature stress impacts both welfare and productivity of livestock. Global warming is expected to increase the impact, especially in tropical areas. We investigated the biological mechanisms regulated by temperature stress due to the circadian temperature cycle in temperature adapted and non-adapted chicken under tropical conditions. We studied transcriptome profiles of heart, breast muscle, and spleen tissues of Ethiopian lowland chicken adapted to high circadian temperatures and non-adapted Ethiopian highland chicken under lowland conditions at three points during the day: morning, noon, and evening. Functional annotations and network analyses of genes differentially expressed among the time points of the day indicate major differences in the reactions of the tissues to increasing and decreasing temperatures, and also the two chickens lines differ. However, epigenetic changes of chromatin methylation and histone (de)acetylation seemed to be central regulatory mechanisms in all tissues in both chicken lines. Finally, all tissues showed differentially expressed genes between morning and evening times indicating biological mechanisms that need to change during the night to reach morning levels again the next day.</p