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Relationship: 2608

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

Increased, DNA damage and mutation leads to Inadequate DNA repair

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, DNA damage and mutation

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
Alcohol Induced DNA damage and mutations leading to Metastatic Breast Cancer	adjacent	High	High	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development

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
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Female	High

Life Stage Applicability

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

Term	Evidence
Not Otherwise Specified	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

Upstream event: Increased, DNA damage and mutation

Downstream event: DNA repair mechanism, Reduced

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

Despite the fact that OGG1's dual activity as a glycosylase and lyase has been widely acknowledged and proved experimentally, investigations suggest that apurinic endonuclease 1 is primarily responsible for the cleavage of phosphodiester link 5' to the lesion (APE1) (Allgayer et al., 2016; R. Wang et al., 2018). In rare circumstances, APE1 may be the primary driver of BER intermediate buildup. According to some research, OGG1 is involved in the repair of non-transcribed strands but isn't essential for transcription-coupled 8-oxo-dG repair.; Le Page et al. reported efficient repair of 8-oxo-dG in the transcribed sequence in Ogg1 knockout mouse cells (Le Page et al., 2000). Furthermore, the repair of 8-oxo-dG is influenced by the sequences surrounding it; the location of the lesions may have a negative impact on repair effectiveness. (Pastoriza-Gallego et al., 2007). We note that the study by Allgayer et al. was investigating the fate and effect of 8-oxo-dG during transcription; repair mechanism may vary by situation and availability of repair enzymes at the time.

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

DNA repair mechanism depends on the cell type,age of the cell and extra cellular environment.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The specific relationship between oxidative DNA lesions and when repair is regarded insufficient has yet to be determined; this relationship will most likely differ between cell types and tissues, making it difficult to define. There are computational models of 8-oxo-dG repair kinetics.

To explore the rate of clearance of BER repair intermediates, Sokhansanj and Wilson III [2004] used a quantitative model of BER and a literature estimate for the rate of generation of endogenous 8-oxo-dG (Sokhansanj and Wilson III, 2004).

The OGG1, AP lyases, polymerases, and ligases activities were incorporated in the BER model, which used Michaelis-Menten enzyme kinetics.
The model assumed that endogenous oxidative lesions formed at a rate of 500 8-oxo-dG/day.
- Based on the information above, it was calculated that after a sudden increase in 8-oxo-dG to 20,000 8-oxo-dG/cell, the total amount of repair intermediates would revert to baseline in 4000 seconds (less than 1 hour)
- This model also assumed that OGG1 was available in excess
The glycosylase reaction kinetics of OGG1 (a bifunctional glycosylase/lyase) were reported to increase when APE1 (AP site endonuclease) was present. It's thought to be because the two enzymes work together.
When OGG1 kinetics were reduced by tenfold, 8-oxo-dG increased tenfold, while no other repair intermediates increased.
Quantitative understanding is represented as below;

	Method/ measurement reference	Reliability	Strength of evidence	Assay fit for purpose	Repeatability/ reproducibility	Direct measure
Rat	Quantification of ATase activity – BSA method APNG assay, OXOG glycosylase activity assay, Western immunoblotting, Immunohistochemical detection of ATase (Kotova et al.,2013)	Yes	Strong	Yes	Yes	Yes
Rat cell line	Flow cytometric micronucleus assay, Cell cycle analysis, Replication fork elongation assay, Cytotoxicity assay, Recombination assay, (Panida et al.,2001)	Yes	Strong	Yes	Yes	Yes
mouse	FISH karyotyping, Invivo point mutation assay, Whole genome sequencing of HSC clones (Garayacoechea et al.,2012)	Yes	Strong	Yes	Yes	Yes

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Linear increase in DNA damage was noted following exposure to the stressor.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Changes were noted within 24 hours of treatment with the stressor, however after withdrawl of the stressor, persisted for 3-4 weeks.

The acute ethanol dose significantly inhibited O⁶-alkylguanine-DNA alkyltransferase (ATase) activity by 21–32% throughout the 24-h post-treatment period and this was confirmed by immunohistochemical detection of the ATase protein in hepatic nuclei. Twelve hours after the ethanol treatment, the activities of the DNA glycosylases, alkylpurine-DNA-N-glycosylase (APNG) and 8-oxoguanine-DNA glycosylase (OXOG glycosylase) were each increased by ~44%. In contrast, when given chronically via the liquid diet, ethanol initially had no effect on ATase activity, but after 4 weeks ATase activity was increased by 40%. Following ethanol withdrawal, ATase activity remained elevated for at least 12 h, but, by 24 h, the activity had fallen to the uninduced control level. DNA glycosylase activities were again affected differently. After 1 week of dietary ethanol exposure, there was no effect on APNG activity but it was inhibited by 19% at 4 weeks. OXOG glycosylase activity, on the other hand, was increased by 53% after 1 week, but decreased by 40% after 4 weeks.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not found to the best of our knowledge.

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

In any eukaryotic or prokaryotic cell, oxidative DNA damage can develop and overwhelm the cell's repair processes. This KER has been seen in mammalian cells, yeast, and bacteria, among other places.