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OECD Series on Adverse Outcome Pathways

An Adverse Outcome Pathway (AOP) describes a logical sequence of causally linked events at different levels of biological organisation, which follows exposure to a chemical and leads to an adverse health effect in humans or wildlife. AOPs are the central element of a toxicological knowledge framework, promoted by member countries through OECD, built to support chemical risk assessment based on mechanistic reasoning. These AOPs are available in the AOP Wiki, an interactive and virtual encyclopaedia for AOP development. Following their development and review, the endorsed AOPs are published the OECD Series on Adverse Outcome Pathways. As scientific knowledge progresses, the publication of an AOP in this series does not preclude the regular update or new contributions to a given AOP in the AOP Wiki. While the AOP Wiki is a dynamic tool, only impactful changes to the AOP will be reflected in subsequent updates of the published AOP. The number 1 in the OECD Series on Adverse Outcome Pathways is the Users’ Handbook, which is a supplement to the Guidance Document for developing and assessing AOPs. This handbook contains an updated template for AOP development and provides focused and practical instructions for both AOP developers and reviewers.

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Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations

Germ cell/heritable mutations are important regulatory endpoints for international agencies interested in protecting the health of future generations. However, germ cell mutation analysis has been hampered by a lack of efficient tools. The motivation for developing this AOP was to provide context for new assays in this field, identify research gaps and facilitate the development of new methods. In this AOP, a compound capable of alkylating DNA is delivered to the testes causing germ cell mutations and subsequent mutations in the offspring of the exposed parents. Although there are some gaps surrounding some mechanistic aspects of this AOP, the overarching AOP is widely accepted and applies broadly to any species that produces sperm.

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Keywords: DNA adducts, DNA alkylation, DNA repair, heritable mutations, male pre-meiotic germ cells
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