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

Rémi Terranova, Antonio Vitobello, Alberto Del Rio Espinola, C. Roland Wolf, Michael Schwarz, John M. Thomson, Richard Meehan, Jonathan G. Moggs

    Research output: Contribution to journalReview article

    6 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)62-70
    Number of pages9
    JournalCurrent Opinion in Toxicology
    Volume3
    DOIs
    Publication statusPublished - Apr 2017

    Fingerprint

    Xenobiotics
    Epigenomics
    Carcinogenesis
    Tissue
    Animals
    Neoplasms
    Risk assessment
    Tumors
    Genes
    Modulation
    DNA sequences
    Genetic Models
    Biomarkers
    Tumor Biomarkers
    Gene expression
    Carcinogens
    Chromatin
    Hazards
    Industry
    Animal Models

    Keywords

    • Cancer risk assessment
    • Epigenetics
    • Epigenome
    • Genetics
    • Non-genotoxic carcinogenesis

    Cite this

    Terranova, Rémi ; Vitobello, Antonio ; Del Rio Espinola, Alberto ; Wolf, C. Roland ; Schwarz, Michael ; Thomson, John M. ; Meehan, Richard ; Moggs, Jonathan G. / Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis. In: Current Opinion in Toxicology. 2017 ; Vol. 3. pp. 62-70.
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    abstract = "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.",
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    Terranova, R, Vitobello, A, Del Rio Espinola, A, Wolf, CR, Schwarz, M, Thomson, JM, Meehan, R & Moggs, JG 2017, 'Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis', Current Opinion in Toxicology, vol. 3, pp. 62-70. https://doi.org/10.1016/j.cotox.2017.06.005

    Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis. / Terranova, Rémi; Vitobello, Antonio; Del Rio Espinola, Alberto; Wolf, C. Roland; Schwarz, Michael; Thomson, John M.; Meehan, Richard; Moggs, Jonathan G.

    In: Current Opinion in Toxicology, Vol. 3, 04.2017, p. 62-70.

    Research output: Contribution to journalReview article

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    T1 - Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis

    AU - Terranova, Rémi

    AU - Vitobello, Antonio

    AU - Del Rio Espinola, Alberto

    AU - Wolf, C. Roland

    AU - Schwarz, Michael

    AU - Thomson, John M.

    AU - Meehan, Richard

    AU - Moggs, Jonathan G.

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