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

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 Vinita Chauhan (send email) Under development: Not open for comment. Do not cite

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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: Moderate 

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

There are several different pathways leading from oxidative stress to lens opacity and it is the progressive accumulation of oxidative damage from several different mechanisms that causes cataracts (Babizhayev et al., 2011). These paths include protein oxidation, lipid peroxidation, increased calcium levels, DNA damage, apoptosis, and gap junction damage. As this is a non-adjacent (indirectly linked) KER, the direct KERs will provide greater detail for the individual pathways. 

The best-studied route is from oxidative stress through protein oxidation, to cataracts. This occurs as ROS oxidize proteins, causing cross-linking, a decrease in solubility, the formation of protein aggregates that scatter light, lens opacities, and finally cataracts (see figure 1 for a list of sources). In a more detailed version, crystallins are the primary lens proteins (Hamada et al., 2014), and they must maintain a specific organization to allow for transparency (Spector, 1995). ROS can oxidize these proteins, removing their sulfhydryl (-SH) groups, as a result, they form non-disulfide bonds and become cross-linked to each other. These molecules are now less water-soluble and therefore clump together, eventually forming large protein aggregates that scatter light, resulting in lens opacity, and cataracts (Ahmad and Haseeb, 2020).  

A → B Van Kuijk, 1991; Liu et al., 2013; Qin et al., 2019; Ahmad & Haseeb, 2020 

B → C Van Kuijk, 1991; Liu et al., 2013; Ahmad & Haseeb, 2020 

C → D Qin et al., 2019; Ahmad & Haseeb, 2020 

D → E Hamada et al., 2017; Qin et al., 2019; Ahmad & Haseeb, 2020 

E → F Li et al., 1995; Spector, 1995; Hamada et al., 2014; Qin et al., 2019 

F → G Spector, 1995; Qin et al., 2019 

A → C Hamada et al., 2014; Qin et al., 2019; Tangvarasittichai & Tangvarasittichai, 2019 

B → E Zhang, 2012; Qin et al., 2019 

B → G Spector, 1995; Karslioǧlu et al., 2005; Liu et al., 2013; Tangvarasittichai & Tangvarasittichai, 2019 

C → E Hamada et al., 2014; Tangvarasittichai & Tangvarasittichai, 2019 

E → G Li et al., 1995; Hamada et al., 2017; Qin et al., 2019 

Figure 1. Pathway for oxidative stress to cataracts passing through protein oxidation. The bottom portion of the figure provides references supporting the various connections. 

  

Another pathway leading from oxidative stress to cataracts is lipid peroxidation (LPO) (Van Kuijk, 1991; Babizhayev et al., 2011; Tangvarasittichai and Tangvarasittichai, 2019; Ahmad and Haseeb, 2020). This is where ROS attack polyunsaturated fatty acids, forming lipid peroxides that damage DNA, cell membranes, and cytosol regions (Babizhayev et al., 2011; Tangvarasittichai and Tangvarasittichai, 2019), this in turn can cause cataracts (Hightower, 1995; Sacca et al., 2009; Babizhayev et al., 2011; Ahmad and Haseeb, 2020). Furthermore, several studies have found increased concentration of LPO products in cataractous lenses (Spector, 1995; Sacca et al., 2009; Babizhayev et al., 2011; Ahmad and Haseeb, 2020) and aqueous-humour samples (Sacca et al., 2009; Ahmad and Haseeb, 2020) as opposed to healthy ones. LPO also has the potential to cause protein aggregates large enough to increase lens opacity. Moreover, products of LPO such as 4-hydroxynonenal (HNE) can induce the fragmentation of lens proteins, increasing lens opacity and ultimately cataracts (Ahmad and Haseeb, 2020). Finally, this process forms a particularly large contribution to the formation of cataracts because only one ROS is required to form several phospholipid hydroperoxides (Babizhayev et al., 2011).  

Oxidative stress can also increase calcium levels in the lens, leading to cataracts (Hightower, 1995; Ahmad and Haseeb, 2020). ROS can change the ionic homeostasis of the lens, increasing the concentration of calcium ions, which activates calpains (Ca2+ dependent cytosolic cysteine proteases), leading to the degradation and aggregation of crystalline proteins (Li et al., 1995; Ahmad and Haseeb, 2020). From there, as shown in figure 1, the aggregation will scatter light, increasing lens opacity, and ultimately causing cataracts.  

An additional mechanism leading from oxidative stress to cataracts is unrepaired DNA damage to the lens epithelial cells (Karslioǧlu et al., 2005; Clement et al., 2012; Liu et al., 2013). Oxidative stress can also cause apoptosis, leading to the induction of cataracts (Li et al., 1995; Mok et al., 2014). Finally, oxidative stress can damage lens gap junctions, therefore causing cataracts. When ROS damage these junctions, it causes changes in intercellular communication, which Ahmad and Haseeb (2020) believe contributes to the formation of cataracts.  

Also of note, the lens uses a variety of antioxidants to protect against oxidative stress. However, the concentration of these antioxidants is lower in cataractous lenses as opposed to healthy ones, which suggests that the cataractous lenses are most likely in a state of oxidative stress (Van Kuijk, 1991; Babizhayev et al., 2011; Varma et al., 2011; Zhang et al., 2012; Tangvarasittichai and Tangvarasittichai, 2019; Ahmad and Haseeb, 2020).  

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, and N-acetylcarnosine  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 
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 
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. 

References

List of the literature that was cited for this KER description. More help

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Liu, F. et al. (2019), “Transcriptional response of murine bone marrow cells to toal-body carbon-ion irradiation”, Mutation Research, Vol. 839, Elsevier B.V, Netherlands, https://doi.org/10.1016/j.mrgentox.2019.01.014 

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