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Relationship: 2819

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, Cell Proliferation leads to Cataracts

Upstream event

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

Increase, Cell Proliferation

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
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	Moderate
Mixed	Moderate
Female	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

Throughout their life, cells replicate their organelles and genetic information before dividing to form two new daughter cells, in a process known as cellular proliferation. This is regulated by the cell cycle, which is subdivided into various stages notably, G1, S, G2, and M in mammals. Progression through the cycle is dependent on sufficient nutrient availability to provide optimal nucleic acid, protein, and lipid levels, as well as sufficient cell mass. If conditions are ideal for division, cells will express genes used for duplicating centrosomes and DNA, eventually leading to cell proliferation (Cuyàs et al., 2014). Various protein complexes, known as cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) regulate passage through each phase. Cyclins will activate specific CDKs, which will phosphorylate and inactive proteins that control passage through the cell cycle. One example is the retinoblastoma protein, which controls passage from G1 to S. Conversely, the CKIs inhibit CDKs, preventing passage through the cell cycle (Lovicu et al., 2014). Disruption of mechanisms in cell cycling can lead to uncontrolled cell proliferation. If this occurs in lens cells, then cataracts can develop. Cataracts are a condition when the lens of the eye develops opacities and becomes cloudy, resulting in blurred vision, faded colors, and reduced night vision (Liu et al., 2017). The lens is a transparent, biconvex tissue located at the front of the eye. It is responsible for focusing light onto the retina, producing a clear image. However, during increased cell proliferation, the lens epithelial cells (LECs) will not differentiate completely, forming lens fiber cells (LFCs) that retain certain organelles. Normal LFCs contain no organelles, rendering them transparent therefore, the incompletely differentiated LFCs form small opacities in the lens (McCarron et al., 2022). As the lens has low metabolic and mitotic activity, there is very little tissue turnover. Therefore, opacities are not removed and accumulate with time (Hamada, 2017).

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)
Anti-proliferative agents	Mitomycin C, octreotide, 5-fluorouracil, doxorubicin, FGF receptor-1 antagonist SU5402, colchicines, and duanomycin	The presence of these compounds can reduce the replication rate of LECs and therefore reduce the risk of cataracts.	Raj et al., 2009
Electric currents	Presence of the currents	The lens of the eye has electric currents flowing from the equator to the posterior and anterior poles. These electric fields help to reduce cell growth. Specifically, they increase the cyclin-Cdk complex inhibitor p27kip1 and decrease the G1-specific cell cycle protein cyclin E. This results in a decrease in the number of cells moving from G1 to S phase in the cell cycle, causing a decrease in proliferation, and therefore a decreased cataract risk.	Wang et al., 2005; Raj et al., 2009

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

Increases in cell proliferation leads to increased lens opacity, which leads to cataracts. The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.

Dose Concordance

Reference	Experiment Description	Result
De Stefano et al., 2021	In vivo. Ptch1+/- /CD1, CD1, Ptch1+/- /C57BI/6, and C57BI/6 mice were exposed to 2 Gy ⁶⁰Co γ-rays at a rate of either 0.3 or 0.063 Gy/min. Ptch1+/- mice have increased cell proliferation. Lens opacity was measured using Scheimpflug analysis.	Mice genetically predisposed towards increased cell proliferation had a maximum lens opacity 2.8x that of typical mice following 2 Gy irradiation.

Incidence Concordance

No studies found

Time Concordance

Reference

Experiment Description

Result

Pendergrass et al., 2010

In vivo. 3-month-old, female, C57BL/6 mice received head-only exposure to 11 Gy X-rays at 2 Gy/min. This initiated cellular proliferation, which was measured by staining and counting nuclei with the vital dye Hoechst 33342. Cataracts were determined through slit lamp analysis.

In mice exposed to 11 Gy X-rays, cellular proliferation began to increase 4 months post-exposure. The mean slit lamp grade (cataract measurement) began to increase at the same time and reached 3.3x control seven months later (Pendergrass et al., 2010).

Hanna & O’Brien, 1963

In vivo. Adult and weanling rats (24 to 29 days old) as well and adult mice were irradiated with to 2400 r of ⁶⁰Co γ-rays at 40 r/min to the left eye. Cell proliferation was detected using thymidine-tritium labelling.

Cells were labelled with thymidine-tritium before the adult animal’s death. This resulted in an increase of about 50% in the number of LECs undergoing DNA synthesis after one month. This was observed 7 to 14 days after irradiation and corresponded to stage I cataract formation.

6 to 12 weeks after irradiation there were almost twice as many labelled cells and the lenses were in stage II cataracts.

These experiments were repeated with rats 24 to 29 days old. The same results were found, but more cells were labelled initially, and cataracts progressed more quickly.

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 requiring a clear lens for vision. The majority of the evidence is from in vivo mice and rats of all ages and does not specify sex. No in vitro evidence was found to support the relationship.