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Relationship: 2817

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

Inadequate DNA repair leads to Cataracts

Upstream event

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

Inadequate DNA repair

Downstream event

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

Cataracts

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
Deposition of energy leading to occurrence of cataracts	non-adjacent	Low	Low	Arthur Author (send email)	Open for citation & comment

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	Low	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Low	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	Moderate
Mixed	Moderate

Life Stage Applicability

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

Term	Evidence
All life stages	Moderate

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

Inadequate repair of DNA is the inability for the cell’s repair machinery to properly maintain correct DNA structure and sequences following the creation of errors (Helleday et al., 2008; Massey & Jones, 2018). Cataracts are herein considered to be the opacification of the lens, and are associated within a reduction in visual acuity (Moreau & King, 2012). DNA repair has several different pathways when functioning correctly. Pathway examples include base excision repair (BER), non-homologous end-joining (NHEJ), nucleotide-excision repair (NER), homologous recombination (HR), and single-strand break repair (SSBR). These pathways are triggered to start when their specific type of DNA lesion is detected (Helleday et al., 2008). Some of these pathways, like NHEJ, are considered to be error-prone (Chiruvella et al., 2013; Hamada & Fujimichi, 2015). The dysregulation and breakdown of these pathways results in the cell having an accumulation of DNA damage (Massey & Jones, 2018). This accumulated genomic damage can lead to improper cellular morphology in lens cells leading to cataracts (Worgul et al., 1989).

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

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

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

N/A

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Genetics	Ptch1	Heterozygosity for Ptch1 increases cataract susceptibility, particularly after exposure to higher radiation doses.	De Stefano et al., 2014; De Stefano et al., 2016; Tanno et al., 2022
Genetics	ATM	Humans carrying the A allele of ATM rs189037 had increased cataract risk.	Gao et al., 2022
Genetics	TP53	Humans carrying the C allele of TP53 had increased cataract risk.	Gao et al., 2022

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 following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.

Dose Concordance

No evidence found.

Incidence Concordance

No evidence found.

Time Concordance

Reference	Experimental Description	Results
Worgul et al., 2002	In vitro, mice lenses exposed to 0.5-4 Gy X-rays with Merriam-Focht grading of cataracts and ATM partial knockouts for inadequate repair.	Vision-impairing cataracts appear 10 weeks earlier in ATM heterozygotes than in wild type animals following 4 Gy X-ray exposure. The heterozygotes had a linear increase, while the wild types had multiple plateaus between their linear increases. At lower dose (0.5 Gy) exposure, low grade cataracts appear in ATM heterozygotes 1 week sooner than wild type animals.
Worgul et al., 2005	In vivo, mice exposed to 1 Gy X-rays in one eye with ATM partial knockouts for inadequate repair and slit-lamp examinations and Merriam-Focht scoring for cataracts.	After 1 Gy X-ray exposure, animals that were heterozygous for ATM developed grade 1 cataracts 3 weeks sooner than wild type animals. Both groups have large increases in incidence once initiated, though both did have a slight drop in numbers early on that was quickly recovered.

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

N/A

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

This KER is plausible in all life stages, sexes, and organisms with DNA and requiring a clear lens for vision. The majority of the evidence is from in vivo adult mice and does not specify sex and weanling mice in vitro models that do not specify sex.