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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
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 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 Do not cite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
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 than 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 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

The biological plausibility of increased cell proliferation leading to cataracts has been reviewed in several articles (Lett et al., 1994; Kleiman et al., 2007; Hamada, 2017; McCarron et al., 2022).  

This KER is specific to lens cells. The GZ is the only area of the lens where cells are undergoing mitosis. After replication, the LECs migrate away, becoming terminally differentiated LFCs. However, if there is excessive cell proliferation, then the LECs will be pushed out of the GZ and forced to become LFCs before they are completely differentiated. This results in LFCs that have not lost all of their organelles, therefore compromising the organelle free zone necessary to retain lens transparency. This process, combined with others such as accumulation of damaged macromolecules throughout life, increases lens opacity (Holsclaw et al., 1994; Lett et al., 1994; Pendergrass et al., 2010; Wiley et al., 2011; Wride, 2011; Fujimichi and Hamada, 2014; Saika et al., 2014; Markiewicz et al., 2015; Ainsbury et al., 2016; Hamada, 2017, McCarron et al., 2022). This process can also be initiated by a decrease in LEC, the remaining cells must therefore replicate more than normal to compensate. As a result, not all differentiation processes proceed properly, increasing the likelihood of cataracts (Ainsbury et al., 2016). 

After the TZ, LECs migrate to the meridional rows, an area below the lens equator, as they are beginning to differentiate into LFCs. In situations with excessive cell proliferation the LFCs that are normally organized in a precise manner will become disorganized. The degree of disorganization also affects lens opacity and can be used as a measure of cataract severity (Holsclaw et al., 1994; Fujimichi and Hamada, 2014; Markiewicz et al., 2015; Hamada, 2017). 

Furthermore, as the lens is a closed system, the damaged cells and macromolecules are not removed and continually contribute to lens opacity, and eventually cataracts (Fujimichi and Hamadaet al., 2014; Ainsbury et al., 2016). 

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 
Response-response Relationship
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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. 

References

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

Ainsbury, E. A. et al. (2016), “Ionizing radiation induced cataracts: recent biological and mechanistic developments and perspectives for future research”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., https://doi.org/10.1016/j.mrrev.2016.07.010 

Bassnett, S. (2014), “Cell biology of lens epithelial cells”, in Lens epithelium and posterior capsular opacification, Springer, Tokyo, https://doi.org/10.1007/978-4-431-54300-8_2 

De Stefano, I. et al. (2021), “Contribution of genetic background to the radiation risk for cancer and non-cancer diseases in Ptch1+/- mice”, Radiation Research, Vol. 197/1, Radiation Research Society, https://doi.org/10.1667/RADE-20-00247.1 

Fujimichi, Y. and N. Hamada (2014), “Ionizing irradiation not only inactivates clonogenic potential in primary normal human diploid lens epithelial cells but also stimulates cell proliferation in a subset of this population”, PloS one, Vol. 9/5, Public Library of Science, United States, https://doi.org/10.1371/journal.pone.0098154 

Hamada, N. (2017), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International journal of radiation biology, Vol. 93/10, Taylor & Francis, England, https://doi.org/10.1080/09553002.2016.1266407 

Hanna, C. and J. E. O’Brien (1963), “Lens epithelial cell proliferation and migration in radiation cataracts”, Radiation research, Academic Press, Inc, United States, https://doi.org/10.2307/3571405 

Holsclaw, D. S. et al. (1994), “Modulating radiation cataractogenesis by hormonally manipulating lenticular growth kinetics”, Experimental eye research, Vol. 59/3, Elsevier Ltd, London, https://doi.org/10.1006/exer.1994.1110 

Kleiman, N. J. et al. (2007), “Mrad9 and Atm haplinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice”, Radiation research, Vol. 168/5, Radiation Research Society, United States, https://doi.org/10.1667/rr1122.1 

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306 

Lett. J. T., A. C. Lee and A. B. Cox (1994), “Risks of radiation cataracts from interplanetary space missions”, Acta astronautica, Vol. 32/11, Elsevier Ltd, England, https://doi.org/10.1016/0094-5765(94)90169-4 

Markiewicz, E. et al. (2015), “Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin K1 expression and lens shape”, Open biology, Vol. 5/4, The Royal Society, England, https://doi.org/10.1098/rsob.150011 

McCarron, R. A. et al. (2022), “Radiation-induced lens opacity and cataractogenesis: a lifetime study using mice of varying genetic backgrounds”, Radiation research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00266.1 

Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular vision, Vol. 16, Molecular Vision, United States, pp. 1496-1513 

Raj et al. (2009), “Post-operative capsular opacification”, Nepalese journal of ophthalmology, Nepal, https://doi.org/10.3126/nepjoph.v1i1.3673 

Saika, S. et al. (2014), Lens epithelium and posterior capsular opacification, Springer, Tokyo.  

Vigneux, G. et al. (2022), “Radiation-induced alterations in proliferation, migration, and adhesion in lens epithelial cells and implications for cataract development”, Bioengineering, MDPI AG, Switzerland, https://doi.org/10.3390/bioengineering9010029 

Wang, E. et al. (2005), “Electrical inhibition of lens epithelial cell proliferation: an additional factor in secondary cataract”, The FASEB journal, Vol. 19/7, Wiley, Hoboken, https://doi.org/10.1096/fj.04-2733fje 

Wiley, L. A. et al. (2011), “The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens”, Disease models & mechanisms, Vol. 4/4, The Company of Biologists Limited, England, https://doi.org/10.1242/dmm.006593 

Wride, M. A. (2011), “Lens fibre cell differentiation and organelle loss: many paths lead to clarity”, Philosophical transactions. Biological sciences, Vol. 366/1568, The Royal Society, England, https://doi.org/10.1098/rstb.2010.0324