Development of the adverse outcome pathway “alkylation of DNA in male premeiotic germ cells leading to heritable mutations” using the OECD's users' handbook supplement
- 22 May 2015
- journal article
- research article
- Published by Wiley in Environmental and Molecular Mutagenesis
- Vol. 56 (9), 724-750
- https://doi.org/10.1002/em.21954
Abstract
The Organisation for Economic Cooperation and Development's (OECD) Adverse Outcome Pathway (AOP) programme aims to develop a knowledgebase of all known pathways of toxicity that lead to adverse effects in humans and ecosystems. A Users' Handbook was recently released to provide supplementary guidance on AOP development. This article describes one AOP-alkylation of DNA in male premeiotic germ cells leading to heritable mutations. This outcome is an important regulatory endpoint. The AOP describes the biological plausibility and empirical evidence supporting that compounds capable of alkylating DNA cause germ cell mutations and subsequent mutations in the offspring of exposed males. Alkyl adducts are subject to DNA repair; however, at high doses the repair machinery becomes saturated. Lack of repair leads to replication of alkylated DNA and ensuing mutations in male premeiotic germ cells. Mutations that do not impair spermatogenesis persist and eventually are present in mature sperm. Thus, the mutations are transmitted to the offspring. Although there are some gaps in empirical support and evidence for essentiality of the key events for certain aspects of this AOP, the overall AOP is generally accepted as dogma and applies broadly to any species that produces sperm. The AOP was developed and used in an iterative process to test and refine the Users' Handbook, and is one of the first publicly available AOPs. It is our hope that this AOP will be leveraged to develop other AOPs in this field to advance method development, computational models to predict germ cell effects, and integrated testing strategies.Keywords
Funding Information
- Canadian Regulatory System for Biotechnology
This publication has 99 references indexed in Scilit:
- Harnessing genomics to identify environmental determinants of heritable diseaseMutation Research - Reviews in Mutation Research, 2013
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- A direct characterization of human mutation based on microsatellitesNature Genetics, 2012
- Rate of de novo mutations and the importance of father’s age to disease riskNature, 2012
- Hepatic mRNA, microRNA, and miR‐34a‐Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutationEnvironmental and Molecular Mutagenesis, 2011
- Clan Genomics and the Complex Architecture of Human DiseaseCell, 2011
- Multifaceted Roles of Alkyltransferase and Related Proteins in DNA Repair, DNA Damage, Resistance to Chemotherapy, and Research ToolsChemical Research in Toxicology, 2011
- Efficiency and fidelity of human DNA polymerases λ and β during gap-filling DNA synthesisDNA Repair, 2011
- Isolated spermatozoa as indicators of mutations transmitted to progenyMutation Research - Reviews in Mutation Research, 2010
- Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogoniaMutation Research - Reviews in Mutation Research, 2007