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Relationship: 2816

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

Modified Proteins leads to Cataracts

Upstream event

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

Modified Proteins

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	adjacent	Moderate	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	Moderate	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Female	Moderate
Male	Moderate

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

The maintenance of the correct structure and location of lens proteins is crucial for the proper refraction of light in the eye. Any modifications to the proteins of the lens can result in a reduction in lens transparency and cataract formation through the mechanism of protein aggregation (Zhao et al., 2015). Cataracts develop as a result of increased opacity of the lens, leading to reduced visual acuity (Moreau & King, 2012). Under normal conditions, lens proteins work to support the eye through chaperones, gap junctional, and structural functions (Ghosh & Chauhan, 2019; NCRP, 2016). Light enters the eye and passes through the crystallin proteins of the lens, which are responsible for 90% of the proteins in a mature lens. These proteins are carefully arranged as to limit their interference with the light, and the lens cells remove their organelles once they are mature to reduces light-scattering (Moreau & King, 2012; Toyama & Hetzer, 2013). Proteins play other roles in the creation of a transparent medium. Beta- and γ-crystallins are structural proteins that ensure the proper inter-protein interactions occur for the maintenance of nuclear transparency, and alpha crystallin proteins chaperone other proteins, including beta- and γ-crystallins, around the lens (Ghosh & Chauhan, 2019; Toyama & Hetzer, 2013). Lens epithelial cells (LEC) rely on proteins, such as connexin43, to act as phenotypic markers to help organize the cells within the lens following proliferation, preventing the cells from improperly layering within the eye. LECs are packed with crystallin proteins. If the connexin43 proteins are altered, that would impair their ability to help organize the LECs properly, resulting in all the proteins found within those LECs to be disoriented compared to the proteins of neighbouring cells (Berthoud et al., 2014). This improper layering of the cells leads to modified transparency in the lens as a result of the disorganization of the many crystallin proteins within the LEC. Connexin proteins typically join chaperone proteins in a complex and repair misfolded proteins (NCRP, 2016). Proteins can be modified from exposure to stressors, and depending on the type of protein, the alteration will also differ. Following modification, proteins will be unable to correctly perform their roles within the lens, such as preventing aggregation via proper chaperone and structural actions. (Ghosh & Chauhan, 2019; Toyama & Hetzer, 2013; NCRP, 2016). Protein aggregation occurs, which is worsened by the inability of the proteins to form complexes to repair themselves, and this leads to reduced lens transparency and increased cataract incidence.

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)
Age	≥ 40 years old (human) has higher incidence of lens opacity	Proteins naturally change and degrade over time however they do not get removed from within the lens’ center. This leads to a higher level of modified protein accumulation within the lens in older individuals. Protein accumulation/aggregation is linked to light scattering and cataracts.	Hains & Truscott, 2010; NCRP, 2016
5-cholesten-3b,25-diol (VP1-001)	Administration of compound	VP1-001 reversed α-crystallin aggregation in vivo, resulting in decreased lens opacity.	Molnar et al., 2019; Wang 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 statistically significant.

Incidence Concordance

Reference	Experiment Description	Result
Menard et al., 1986	In vivo, rats received head-only exposure to 15.3 Gy γ-rays, proteins detected with Lowry assay and size-exclusion liquid chromatography, lens opacity assessed by slit-lamp eye examinations.	In rats exposed in vivo to 15.3 Gy γ-rays, the water-soluble protein make-up in the lens decreased 13.6x (indicating increased levels of modified proteins) and dense cataracts were observed, while controls developed minimal opacification.

Time Concordance

Reference	Experiment Description	Result
Fujii et al., 1986	In vivo, mice received whole-body exposure to 15 Gy X-rays D/L ratio of proteins was determined with gas-liquid chromatography and cataracts determined by the observation of lens opacification.	In mice exposed in vivo to 15 Gy X-rays the ratio of D/L conformation lens proteins increased 1.5x 60 days post-irradiation. Lens opacity increased at the same point in time.

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 that have a clear lens for vision. The majority of the evidence is from in vivo studies (adult mice, and rats) and human cohorts. No in vitro evidence was found to support the relationship.