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Relationship: 2399

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

Bulky DNA adducts, increase leads to Increase, Mutations

Upstream event

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

Bulky DNA adducts, increase

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
Bulky DNA adducts leading to mutations	non-adjacent			Evgeniia Kazymova (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 Do not cite	Under Development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	Link
human and other cells in culture	human and other cells in culture	NCBI
human	Homo sapiens	NCBI
rat	Rattus norvegicus	NCBI
mouse	Mus musculus	NCBI
yeast	Saccharomyces cerevisiae	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

Life Stage Applicability

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

Term	Evidence
All life stages

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

Bulky DNA adducts occur when aromatic compounds are metabolically activated and interact with DNA bases. Not all of these bulky adductsare stable, however some have been found to persist and cause mutations during repair or replication. The specific mutation that occurs variesby bulky DNA adduct and by chemical. Exposure to the benzo(a)pyrene (B(a)P) or its metabolite anti-benzo(a)pyrene diol epoxide (BPDE)leads to (+/-)-trans-anti-BPDE-N-2-dG adducts, these adducts are associated with G→T transversions (Chiapperino et al. 2002; Zhang et al.2000, 2002), the occurrence of these transversions has been observed both in smokers (Anna et al. 2009; Hainaut and Pfeifer 2001) and in non-smokers (DeMarini et al. 2001). Exposure to aristicholic acid (AA) leads to the persistent DNA adduct 7-(deoxyadenosin-N6-yl) aristolactamI (dA–AAI) adducts and leads to AT→TA transversions (Arlt et al., 2002). Exposure to aflatoxin B1 has been leads to 8,9-dihydro-8- (N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) adducts, which can lead to the AFB1-formamidopyrimidine (FAPY) adduct and ultimately causeG→T transversions (Bailey et al. 1996; Smela et al. 2002).

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

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

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

There is some quantitative understanding of the amount of bulky DNA adducts that leads to mutations.

Broschard et al. 1994 and Broschard, Wiessler, and Schmeiser 1995 found that T7 DNA polymerase and with human DNA polymerase α,respectively, paired dA-AAI equally well with A or T, suggesting that there is a 50% chance of a dA-AAI lesion will lead to a mutation.

Zhang et al. 2000 found that polymerase eta predominately incorporated A opposite (+)-trans -anti-BPDE-N²-dG bulky adducts, lessfrequently a T was incorporated and least frequently a G or C was incorporated. Suggesting that it is most likely the persistence of a (+)-trans -anti-BPDE-N² -dG bulky adduct will lead to a mutation of a G to T transversion.

There are also studies demonstrating the quantitative dose-response between bulky DNA adducts and mutations, see Empirical Evidence.

Response-response Relationship

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

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

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

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

Bulky DNA adducts can occur in any cell type that is able to metabolically activate the stressor. Bulky adducts and resulting mutation frequencyhave been observed in various cell lines in vitro (TK6, HeLa, CHO) as well as various organisms in vivo (yeast, rat, human and mouse). This is unspecific to sex and to life stage.