API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1931

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

Increase, DNA strand breaks leads to Increase, Mutations

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Increase, DNA strand breaks
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Mutations

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
Oxidative DNA damage leading to chromosomal aberrations and mutations non-adjacent High Low Brendan Ferreri-Hanberry (send email) Open for comment. Do not cite WPHA/WNT Endorsed
Deposition of energy leading to lung cancer non-adjacent High Low Brendan Ferreri-Hanberry (send email) Open for citation & comment EAGMST Approved

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
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

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

DNA single strand breaks (SSB) are generally repaired rapidly and efficiently. However, if left unrepaired, SSBs can interfere with replication and cause the replication fork to collapse resulting in double strand breaks (DSB). Multiple SSBs in close proximity to each other can also give rise to DSBs. DSBs can be repaired virtually error-free by homologous recombination (HR), which uses DNA sequence in the homologous chromosome or sister chromatid as a template for new strand synthesis (Polo and Jackson, 2011). Alternatively, the broken ends may be joined to other sites in the genome regardless of homology via non-homologous end joining (NHEJ), irreversibly altering the DNA sequence (deletion, addition, rearrangement). Because HR is a more time-consuming and labour-intensive process, larger proportions of DSBs are repaired via NHEJ than via HR (Mao et al., 2008a; Mao et al., 2008b).

Alterations in DNA sequence can also occur from structural damage to the chromosomes; observations of micronucleus indicate chromosomal aberrations and that a permanent loss of DNA segments has occurred.

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

In Kuhne et al. (2005) and Rydberg et al. (2005) studies provided above, mutation was not directly measured. The PFGE and hybridization assay detects a 3.2-Mbp restriction fragment from chromosome 21. Deviation of DNA restriction fragments from the 3.2-Mbp mark during electrophoresis suggests occurrence of breakage and failed reconstruction in this segment of chromosome 21; induction of mutations can be inferred from the change in the size of the restriction fragments. The remaining 22 chromosomes are not considered. This method may not be sensitive enough to detect small base changes.

Cell cycle can influence the repair pathway of DSBs and, thus, the risk of incorrect rejoining of broken ends. In G1 phase, NHEJ may be favoured, while in S, G2, or M phase, both HR and NHEJ have been observed to be active in repair (Mao et al., 2008b). 

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 strand breaks and subsequent mutations can occur in any eukaryotic and prokaryotic cell. Any DNA strand break has potential to cause alterations in DNA sequence (e.g., deletions and insertions), whether it is due to insufficient or faulty repair.