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Review

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

1
Environmental Health Sciences and Research Bureau, Hazard Identification Division, Health Canada, AL:2203B, Ottawa, ON K1A 0K9, Canada
2
CNRS, LIEC, Université de Lorraine, 57070 Metz, France
3
Independent at the Time of Publication, Previously US Food and Drug Administration, Rockville, MD 20852, USA
4
Toxicology Team, Division of Human Food Safety, Center for Veterinary Medicine, US Food and Drug Administration, Department of Health and Human Services, Rockville, MD 20852, USA
5
German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessment, Diedersdorfer Weg 1, 12277 Berlin, Germany
6
Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton OX11 0RQ, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Ashis Basu
Int. J. Mol. Sci. 2021, 22(20), 10969; https://doi.org/10.3390/ijms222010969
Received: 25 August 2021 / Revised: 30 September 2021 / Accepted: 4 October 2021 / Published: 11 October 2021
Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system occur in cancers whether the initial carcinogenic events are from genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens. NGTxC are not inherently DNA reactive, they do not have a unifying mode of action and as yet there are no regulatory test guidelines addressing mechanisms of NGTxC. To fil this gap, the Test Guideline Programme of the Organisation for Economic Cooperation and Development is developing a framework for an integrated approach for the testing and assessment (IATA) of NGTxC and is considering assays that address key events of cancer hallmarks. Here, with the intent of better understanding the applicability of epigenetic assays in chemical carcinogenicity assessment, we focus on DNA methylation and histone modifications and review: (1) epigenetic mechanisms contributing to carcinogenesis, (2) epigenetic mechanisms altered following exposure to arsenic, nickel, or phenobarbital in order to identify common carcinogen-specific mechanisms, (3) characteristics of a series of epigenetic assay types, and (4) epigenetic assay validation needs in the context of chemical hazard assessment. As a key component of numerous NGTxC mechanisms of action, epigenetic assays included in IATA assay combinations can contribute to improved chemical carcinogen identification for the better protection of public health. View Full-Text
Keywords: epigenetics; DNA methylation; histone modifications; carcinogens; non-genotoxic; risk assessment; mode of action; IATA; AOP epigenetics; DNA methylation; histone modifications; carcinogens; non-genotoxic; risk assessment; mode of action; IATA; AOP
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MDPI and ACS Style

Desaulniers, D.; Vasseur, P.; Jacobs, A.; Aguila, M.C.; Ertych, N.; Jacobs, M.N. Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications. Int. J. Mol. Sci. 2021, 22, 10969. https://doi.org/10.3390/ijms222010969

AMA Style

Desaulniers D, Vasseur P, Jacobs A, Aguila MC, Ertych N, Jacobs MN. Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications. International Journal of Molecular Sciences. 2021; 22(20):10969. https://doi.org/10.3390/ijms222010969

Chicago/Turabian Style

Desaulniers, Daniel, Paule Vasseur, Abigail Jacobs, M. C. Aguila, Norman Ertych, and Miriam N. Jacobs. 2021. "Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications" International Journal of Molecular Sciences 22, no. 20: 10969. https://doi.org/10.3390/ijms222010969

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