API

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Relationship: 24

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Alkylation, DNA leads to Inadequate DNA repair

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Alkylation, DNA
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Inadequate DNA repair

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations adjacent High Moderate Evgeniia Kazymova (send email) Open for citation & comment WPHA/WNT Endorsed
Alkylation of DNA leading to cancer 1 adjacent High Moderate Arthur Author (send email) Open for adoption
Alkylation of DNA leading to reduced sperm count adjacent Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Syrian golden hamster Mesocricetus auratus Moderate NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Alkylated DNA may be tolerated and/or repaired error-free by a variety of DNA repair pathways. However, at high doses, it is established that the primary DNA repair pathway (O6-Alkylguanine-DNA alkyltransferase: AGT) responsible for removing alkylated DNA becomes saturated. This may lead to several potential adduct fates: (i) error-free repair of the DNA adduct using alternative DNA repair mechanisms; (ii) no repair (DNA damage is retained); or (iii) instability in the DNA duplex leading to DNA strand breaks and possibly activation of DNA damage signaling. For repair of alkyl adducts it is well established that the O6-alkylguanine-DNA alkyltransferase pathway becomes saturated at high doses leading to insufficient repair at high doses.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

DNA repair is not generally measured directly; thus, insufficient repair is inferred from the retention of adducts or the induction of increases in mutation frequencies post-exposure. In addition, various sizes of alkylation groups (e.g., methyl, ethyl, propyl) can be involved. Although it appears that the larger alkyl adducts tend to be more mutagenic (Beranek, 1990), this is not completely established and there are insufficient data to establish that this is true for germ cells. However, in general, this KER is biologically plausible, broadly accepted for alkyl adducts and has few uncertainties. The direct measurement of insufficient repair can be considered a data gap.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

DNA adducts can occur in any cell type. While there are differences across taxa, all species have some DNA repair systems in place and it is common to extrapolate conclusions across eukaryotic species.