To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2819
Increase, Cell Proliferation leads to Cataracts
Key Event Relationship Overview
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 Do not cite|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
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
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
Overall Weight of Evidence: Moderate
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
Known modulating factors
|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|
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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