Targets and mechanisms of chemically induced aneuploidy. Part 1 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases
- DOI
- Language of the publication
- English
- Date
- 2019-03-02
- Type
- Article
- Author(s)
- Lynch, Anthony M.
- Eastmond, David
- Elhajouji, Azeddine
- Froetschl, Roland
- Kirsch-Volders, Micheline
- Marchetti, Francesco
- Masumura, Kenichi
- Pacchierotti, Francesca
- Schuler, Maik
- Tweats, David
- Publisher
- Elsevier
Abstract
An aneuploidy workgroup was established as part of the 7th International Workshops on Genotoxicity Testing. The workgroup conducted a review of the scientific literature on the biological mechanisms of aneuploidy in mammalian cells and methods used to detect chemical aneugens. In addition, the current regulatory framework was discussed, with the objective to arrive at consensus statements on the ramifications of exposure to chemical aneugens for human health risk assessment. As part of these efforts, the workgroup explored the use of adverse outcome pathways (AOPs) to document mechanisms of chemically induced aneuploidy in mammalian somatic cells. The group worked on two molecular initiating events (MIEs), tubulin binding and binding to the catalytic domain of aurora kinase B, which result in several adverse outcomes, including aneuploidy. The workgroup agreed that the AOP framework provides a useful approach to link evidence for MIEs with aneuploidy on a cellular level. The evidence linking chemically induced aneuploidy with carcinogenicity and hereditary disease was also reviewed and is presented in two companion papers. In addition, the group came to the consensus that the current regulatory test batteries, while not ideal, are sufficient for the identification of aneugens and human risk assessment. While it is obvious that there are many different MIEs that could lead to the induction of aneuploidy, the most commonly observed mechanisms involving chemical aneugens are related to tubulin binding and, to a lesser extent, inhibition of mitotic kinases. The comprehensive review presented here should help with the identification and risk management of aneugenic agents.
Plain language summary
Health Canada supports the development, validation and improvement of test guidelines for the Organisation for the Economic Co-operation and Development (OECD). These guidelines are routinely used for assessing chemicals for mutagenicity (changes in the sequence of the DNA) or clastogenicity (induction of breaks in the DNA). However, guidelines are not yet available to properly assess the ability of chemicals to induce changes in chromosome number, a condition called aneuploidy and that is associated with cancer development and hereditary diseases such as Down syndrome. To address this gap, a group of international experts from various governments, industry and academia met in Tokyo, Japan in November 2017 as part of the International Workshops on Genotoxicity Testing, to discuss the role of aneugens (chemicals that induce aneuploidy) in human health risk assessment. The work from the group is summarized in three companion papers. In this first paper, the group conducted a review of the scientific literature and developed scientific consensus on the biological mechanisms by which chemicals can induce aneuploidy, identified the best methodologies that can be used to measure aneuploidy, and explored the use of the OECD Adverse Outcome Pathway approach, which is an effort to describe all molecular events that take place from the initial interaction of a chemical with a biological structure to an adverse outcome, to document mechanisms of chemically induced aneuploidy. The group concluded that the tests that are currently used to generated data for regulatory submission, while not ideal for a comprehensive risk assessment, are sufficient for the identification of chemicals that may be capable of inducing aneuploidy. The comprehensive review presented in this paper should help regulators in the identification and risk management of aneugens.
Subject
- Health,
- Health and safety