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Published on: February 24, 2015
Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation
Daniel Desaulniers1, Paule Vasseur2, Abigail Jacobs3
1Environmental Health Sciences and Research Bureau, Hazard Identification Division, Health Canada, AL:2203B, Ottawa, ON K1A 0K9, Canada.
Abstract:
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.
Insights
Epigenetic assays, focusing on DNA methylation and histone modifications, can improve the identification of non-genotoxic carcinogens (NGTxC). These assays are crucial for the OECD
Area of Science:
- Environmental epigenetics
- Chemical carcinogenesis
- Toxicology
Background:
- Epigenetic alterations, including DNA methylation and histone modifications, are key drivers of carcinogenesis alongside DNA mutations.
- Carcinogenesis can be initiated by genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens, with NGTxC lacking standardized regulatory testing guidelines.
- The Organisation for Economic Cooperation and Development (OECD) is developing an integrated approach for testing and assessment (IATA) of NGTxC, incorporating assays for cancer hallmarks.
Purpose of the Study:
- To evaluate the applicability of epigenetic assays in chemical carcinogenicity assessment.
- To review epigenetic mechanisms in carcinogenesis and alterations induced by specific NGTxC (arsenic, nickel, phenobarbital).
- To assess the characteristics and validation needs of epigenetic assays for chemical hazard assessment.
Main Methods:
- Review of epigenetic mechanisms in carcinogenesis.
- Analysis of epigenetic alterations following exposure to arsenic, nickel, and phenobarbital.
- Evaluation of epigenetic assay types and their validation requirements.
Main Results:
- Epigenetic alterations are integral to carcinogenesis, irrespective of the initiating carcinogen type (GTxC or NGTxC).
- Specific epigenetic modifications were observed following exposure to arsenic, nickel, and phenobarbital, suggesting potential common or specific mechanisms.
- Epigenetic assays, particularly those measuring DNA methylation and histone modifications, show promise for inclusion in NGTxC assessment frameworks.
Conclusions:
- Epigenetic assays are valuable tools for understanding NGTxC mechanisms of action.
- Incorporating epigenetic assays into IATA frameworks can enhance the identification of chemical carcinogens.
- Improved identification of chemical carcinogens through epigenetic assays contributes to better public health protection.
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