Chemically induced aneuploidy in germ cells. Part II 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
- 2019-03-20
- Type
- Article
- Author(s)
- Pacchierotti, Francesca
- Masumura, Kenichi
- Eastmond, David A.
- Elhajouji, Azeddine
- Froetschl, Roland
- Kirsch-Volders, Micheline
- Lynch, Anthony
- Schuler, Maik
- Tweats, David
- Marchetti, Francesco
- Publisher
- Elsevier
Abstract
As part of the 7th International Workshops on Genotoxicity Testing held in Tokyo, Japan in November 2017, a workgroup of experts reviewed and assessed the risk of aneugens for human health. The present manuscript is one of three manuscripts from the workgroup and reports on the unanimous consensus reached on the evidence for aneugens affecting germ cells, their mechanisms of action and role in hereditary diseases. There are 24 chemicals with strong or sufficient evidence for germ cell aneugenicity providing robust support for the ability of chemicals to induce germ cell aneuploidy. Interference with microtubule dynamics or inhibition of topoisomerase II function are clear characteristics of germ cell aneugens. Although there are mechanisms of chromosome segregation that are unique to germ cells, there is currently no evidence for germ cell-specific aneugens. However, the available data are heavily skewed toward chemicals that are aneugenic in somatic cells. Development of high-throughput screening assays in suitable animal models for exploring additional targets for aneuploidy induction, such as meiosis-specific proteins, and to prioritize chemicals for the potential to be germ cell aneugens is encouraged. Evidence in animal models support that: oocytes are more sensitive than spermatocytes and somatic cells to aneugens; exposure to aneugens leads to aneuploid conceptuses; and, the frequencies of aneuploidy are similar in germ cells and zygotes. Although aneuploidy in germ cells is a significant cause of infertility and pregnancy loss in humans, there is currently limited evidence that aneugens induce hereditary diseases in human populations because the great majority of aneuploid conceptuses die in utero. Overall, the present work underscores the importance of protecting the human population from exposure to chemicals that can induce aneuploidy in germ cells that, in contrast to carcinogenicity, is directly linked to an adverse outcome.
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 second paper, the group conducted a review of the scientific literature on the chemical induction of aneuploidy in female (egg) and male (sperm) germ cells. Overall the group agreed that: 1) there is sufficient evidence for supporting the ability of chemicals to induce aneuploidy in germ cells; 2) although there are mechanisms that are unique to germ cells, there is currently no evidence for chemicals that induce aneuploidy in germ cells only; 3) there is clear evidence in animal models that exposure to aneugens leads to transmission of the aneuploidy condition to the offspring. The comprehensive review presented in this paper underscores the importance of protecting the human population from exposure to chemicals that can induce aneuploidy in germ cells which is directly linked to adverse reproductive outcomes. The information provided in this paper is intended to help regulators identify and risk manage aneugens.
Subject
- Health,
- Health and safety