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Relationship: 2818

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

Oxidative Stress leads to Cataracts

Upstream event

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

Oxidative Stress

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

Sex Applicability

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

Sex	Evidence
Mixed	Moderate
Female	Moderate
Unspecific	Low

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

Oxidative stress refers to a state in which the amount of reactive oxygen (ROS) and nitrogen (RNS) species overwhelms the cells antioxidant defense system. This loss in redox homeostasis can lead to oxidative damage to proteins, lipids, and nucleic acids (Schoenfeld et al., 2012; Tangvarasittichai & Tangvarasittichai, 2019; Turner et al., 2002). ROS are molecules with oxygen as the functional center and at least one unpaired electron in the outer orbits. Organisms contain a defense system of antioxidants to help manage ROS levels. When the antioxidant system is overwhelmed by the amount of ROS, the cell can enter a state of oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Karimi et al., 2017).

For the purposes of this KER, cataracts are assumed to have occurred once over 5% of the lens is opaque. Increased ROS levels can damage proteins, lipids, and important cellular processes. If this occurs in the eye, it can lead to cataracts, ss there is very little cell turnover in the ocular lens. The damages accumulates, eventually reaching a point when the opacity of the lens prevents light from passing freely (Tangvarasittichai and Tangvarasittichai, 2019). Over time, enough of the lens (5%) may become opaque, causing cataracts, acondition where the normally clear lens becomes opaque, resulting in blurry, impaired vision and eventually blindness.

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

There are several uncertainties and inconsistencies pertaining to this KER.

It is typically assumed that lens glutathione reductase activity (helps protect against oxidative stress) decreases with age however, one paper contradicts this finding. As an organism ages, the mass of fiber cells, which are metabolically inactive, increases. Spector suggests that this results in an apparent decrease in glutathione reductase activity, leaving the actual activity constant (1995).

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)
Antioxidants	Vitamin C, vitamin E, micronutrients, β-carotene, ascorbic acid, polyphenols, phytate, SOD, pyruvate, xanthine alkaloids, peroxiredoxin 6, anthocyanin, melatonin, N-acetylcysteine (NAC), N-acetylcysteine amide (NACA), and N-acetylcarnosine (NC)	Adding antioxidants decreases the occurrence and progression of cataracts.	Karslioǧlu et al., 2005; Sacca et al., 2009; Babizhayev et al., 2011; Varma et al., 2011; Hamada et al., 2014; Mok et al., 2014; Lee & Afshari, 2023
Age	Increased age	Cataracts is due to an accumulation of small opacities in the lens, which increases with age. Furthermore, the concentration of various antioxidants such as GSH also decrease with age, increasing the lens’ vulnerability to oxidative stress. Younger lenses also show better recovery after oxidative stress, possibly due to higher levels of thioltransferase and thioredoxin and increased ability to upregulate appropriate genes.	Spector, 1995; Sacca et al., 2009; Zhang et al., 2012; Ahmad and Haseeb, 2020
Genetics	Variations in the genes coding for antioxidant enzymes such as SOD, GPX, and catalase. An example includes the G/G genotype of the SOD1-251A/G polymorphism.	Mutations in critical genes can reduce cell protective capacity to handle oxidative stress, and therefore the formation of lens opacities.	Tangvarasittichai and Tangvarasittichai, 2019
Oxygen	Increased oxygen levels	Higher oxygen concentrations increase oxidative stress, and therefore the risk of cataracts.	Blakely, 2012; Hamada and Sato; 2016; Richardson, 2022
Diabetes/ hyperglycemia	Diabetes/hyperglycemia diagnosis	These conditions increase oxidative stress and therefore the risk of cataracts. They increase mitochondrial production of ROS and decreases glutathione regeneration. Additionally, these effects have been found to continue even after hyperglycemia has been returned to euglycemia in a phenomenon known as metabolic memory.	Qin et al., 2019
Lanosterol and its derivatives	Increased lanosterol levels	Lanosterol and its derivatives can depolymerize protein aggregates, which reduces lens opacity and can help to reverse cataract development. However, this has not been tested in humans.	Qin et al., 2019

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 level of quantitative understanding for this KER is low. Studies examine the relationship between various oxidative stress inducers, such as H₂O₂ and radiation, and either lens opacity/cataracts, or indirect indicators such as visual quality. The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.

Dose Concordance

Reference	Experiment Description	Result
Karslioǧlu et al., 2005	In vivo. Female, 8–12-week-old, Sprague-Dawley rats received head-only exposure to 5 Gy of ⁶⁰Co γ-rays at 0.59 Gy/min to induce oxidative stress, measured via the presence of malondialdehyde (MDA). Cataracts were characterised using the lens opacities classification system, version III (LOCS III).	Rats exposed in vivo to 5 Gy of ⁶⁰Co γ-rays displayed a 68.9% increase in malondialdehyde levels (indicative of increased oxidative stress) and a 90% increase in cataract prevalence relative to control.

Incidence Concordance

No studies found.

Time Concordance

Reference	Experiment Description	Result
Qin et al., 2019	In vitro. Human urinary cell-derived induced pluripotent stem cells were differentiated to form lentoid bodies. These were then exposed to 500 μM/day of H₂O₂ to induce oxidative stress. Cataract progression was measured via light microscopy and mean gray values (light intensity, where a lower gray value indicates increased opacity).	Exposure to oxidative stress induced an approximately linear 1.2x decrease in the mean gray value compared to control over the course of 20 days.
Liu et al., 2013	In vitro. 4 porcine lenses were exposed in vitro to 2 mM of H₂O₂, an ROS known to cause oxidative stress. Lens opacity was measured after one and four days.	In porcine lenses exposed in vitro to 2 mM of H₂O₂ (induces oxidative stress), lens opacity increased to 20x control one day post-exposure.

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

The main endogenous source of ROS production is the electron transport chain (ETC) in the mitochondria (Babizhayev et al., 2011). The mitochondrial DNA (mtDNA) responsible for the ETC is vulnerable to oxidative damage because it lacks protective proteins and histones. It is also located near the main source of endogenous ROS, the electron transport chain. Furthermore, some ROS have very short half-lives, meaning that they cannot travel very far. For example, hydroxyl radicals have half-lives in the order of 10-9 s. When mtDNA is damaged, the electron transport chain dysfunctions that create ROS become more common. This creates a feedforward loop where oxidative stress causes oxidative damage to mtDNA, which then causes the production of more ROS, increasing the oxidative stress in a vicious cycle (Lee et al., 2004; Zhang et al., 2010; Tangvarasittichai and Tangvarasittichai, 2019; Ahmad and Haseeb, 2020).

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 with no specification on sex, as well as using human in vitro models that do not specify sex.