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Energy Deposition leads to Increase, Oxidative DNA damage
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||non-adjacent||Moderate||Moderate||Vinita Chauhan (send email)||Open for citation & comment|
Life Stage Applicability
|All life stages||Low|
Key Event Relationship Description
Energy can be deposited onto biomolecules stochastically from various forms of radiation. As radiation passes through an organism, it loses energy; potentially causing direct and indirect molecular-level damage in the process. The extent of damage occurs at various levels depending on ionization and non-ionization events (excitation of molecules). Reaction with water molecules can produce reactive oxygen species (ROS). Additionally, enzymes involved in reactive oxygen and nitrogen species (RONS) production can be directly upregulated (de Jager, Cockrell & Plessis, 2017). When one ROS interacts with the DNA, it produces DNA-protein cross-links, inter and intra-strand links, and tandem base lesions. When at least two ROS associate with DNA it produces oxidatively generated clustered DNA lesions (OCDLs), more complex damage. This can include single and double strand breaks, abasic sites, and oxidized bases (Cadet et al., 2012), which can lead to chromosomal aberrations, cytotoxicity, and oncogenic transformations (Stohs, 1995) as well as structural changes to the DNA, blocking polymerases (Zhang et al., 2010). Cells contain DNA repair mechanisms that help lessen the damage, but they are not perfect and can lead to insufficient repair , resulting in sustained damage (Eaton, 1995; Ainsbury et al., 2016; Markkanen, 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
As energy is deposited in an organism, it produces ROS (Pendergrass et al., 2010; Cheng, 2019). As their formation is highly regulated, any changes can be undesirable, inducing a state of oxidative stress where cellular defense mechanisms, such as antioxidants, are overwhelmed by ROS levels (Brennan & Kantorow, 2009). A low level of DNA damage constantly exists in healthy cells, with cells acquiring an estimated 70 000 lesions per day, mostly due to ROS produced during normal metabolism and base hydrolysis (Amente et al., 2019). This number increases under oxidative stress (Lee et al., 2004). If cells replicate, any damage to their DNA that is not correctly repaired is passed on to their descendants (Wolf et al., 2008). Furthermore, these mechanisms and outcomes may vary dependent on the stressor. Different stressors may interact and produce a greater than additive effect (Di Girolamo, 2010). For example, singlet oxygen plays an important role in activating mitogen-activated protein kinases (MAPKs), which act as signal transducers to initiate DNA damage.
Throughout this process, DNA repair pathways are also activated. These include the nucleotide excision repair (NER) pathway (Mesa, 2013), and the base excision repair (BER) pathway (Cheng et al., 2019). They can repair certain amounts of damage but may become overwhelmed when faced with large numbers of DNA lesions (Lee et al., 2004). Different lesions are also repaired at different rates or with different amounts of fidelity, which can affect the amount of residual damage. For example, DNA single strand breaks are usually repaired quickly (Collins, 2014), while double strand breaks are more complex and are therefore less likely to be repaired correctly (Schoenfeld et al., 2012; Markkanen 2017). The efficiency and effectiveness of the repair pathways will influence the amount of residual oxidative DNA damage.
Uncertainties and Inconsistencies
There are several uncertainties for this KER.
- Some of the data indicates that oxidative DNA damage increases as the time since exposure (Pendergrass et al., 2010; Mesa and Bassnett, 2013). However, other data found a very slight decrease (Mesa and Bassnett, 2013).
- Certain studies found that doses less than 0.5 Gy decrease ROS levels in a non-significant manner. This is thought to be due to radio-tolerance, where low doses induce defense mechanisms, such as glutathione or superoxide dismutase. As the dose is low, these defenses can overcome the effects of radiation, but as doses increase, they become overwhelmed, leading to increases in ROS levels (Bahia et al., 2018). These changes subsequently cause a similar pattern in DNA oxidative damage that dips between 0 and 0.5 Gy, where it begins to slowly increase (Bahia et al., 2018; Cheng et al., 2019).
Known modulating factors
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
|Antioxidants||Increased concentration, examples of antioxidants studied include glutathione and superoxide dismutase||Antioxidants scavenge ROS, resulting in a decrease in oxidative DNA damage.||Pendergrass et al., 2010; Bahia et al., 2018|
|UV absorbing contact lenses||Examples include senofilcon A||Helps to protect the eye against high doses of UVA, therefore decreasing oxidative DNA damage.||Giblin et al., 2012|
|Xeroderma pigmentosum||Presence of the genetic condition||Increases sensitivity to UV-induced oxidative DNA damage by affecting the nucleotide excision repair system.||Di Girolamo, 2010|
|lncRNA H19||Knockdown of lncRNA H19||Increases sensitivity to UVB-induced oxidative DNA damage by affecting the nucleotide excision repair system.||Cheng et al., 2019|
|Low radiation doses||Radiotolerance||Cells may display radio-tolerance by activating ROS scavenger defense mechanisms at low doses, resulting in a decrease in ROS levels and therefore a decrease in oxidative DNA damage, compared to the control. However, at higher doses these defenses are overwhelmed, and ROS levels rise.||Bahia et al., 2018|
|Replication rate||Increased replication||Cells that are actively replicating have increased rates of photolesion repair, and therefore, lower rates of oxidative DNA damage, as opposed to quiescent cells.||Mesa & Bassnett, 2013|
As the time since irradiation increases, damage levels slowly increase during the first few months, but begin to rise more quickly as time passes (Pendergrass et al., 2010; Mesa and Bassnett, 2013).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from in vivo female mice and rabbits, and female human and mice in vitro models.
Ainsbury, E. A. et al. (2021), “Radiation-induced lens opacities: Epidemiological, clinical and experimental evidence, methodological issues, research gaps and strategy”, Environment international, Vol. 146, Elsevier Ltd, Netherlands, https://doi.org/10.1016/j.envint.2020.106213
Amente, S. et al. (2019), “Genome-wide mapping of 8-oxo-7,8-dihydro-2’-deoxyguanosine reveals accumulation of oxidatively-generated damage at DNA replication origins within transcribed long genes of mammalian cells”, Nucleic Acids Research 2019, Vol. 47/1, Oxford University Press, England, https://doi.org/10.1093/nar/gky1152
Bahia, S. et al. (2018), “Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays”, International journal of radiation biology, Vol. 94/4, England, https://doi.org/10.1080/09553002.2018.1439194
Brennan, L. A. and M. Kantorow (2009), “Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degernerations”, Experimental Eye Research, Vol. 88/2, Elsevier Ltd, England, https://doi.org/10.1016/j.exer.2008.05.018
Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327/1, Elsevier Ireland Ltd, Ireland, https://doi.org/10.1016/j.canlet.2012.04.005
Cheng, T. et al. (2019), “lncRNA H19 contributes to oxidative damage repair in the early age-related cataract by regulating miR-29a/TDG axis”, Journal of cellular and molecular medicine, Vol. 23/9, Wiley Subscription Services, Inc. England, https://doi.org/10.1111/jcmm.14489
Collins, A. R. (2014), “Measuring oxidative damage to DNA and its repair with the comet assay”, Biochimica et biophysica acta. General subjects, Vol. 1840/2, Elsevier B.V., https://doi.org/10.1016/j.bbagen.2013.04.022
de Jager, T.L., Cockrell, A.E., Du Plessis, S.S. (2017), “Ultraviolet Light Induced Generation of Reactive Oxygen Species”, in Ultraviolet Light in Human Health, Diseases and Environment. Advances in Experimental Medicine and Biology, Springer, Cham, https://doi.org/10.1007/978-3-319-56017-5_2
Di Girolamo, N. (2010), “Signalling pathways activated by ultraviolet radiation: role in ocular and cutaneous health”, Current pharmaceutical Design, Vol. 16/12, Benthem Science Publishers Ltd, https://doi.org/10.2174/1381-6128/10
Eaton, J. W. (1995), “UV-mediated cataractogenesis: a radical perspective”, Documenta ophthalmologica, Vol. 88/3-4, Springer, Dordrecht, https://doi.org/10.1007/BF01203677
Giblin, F. J. et al. (2012), “A class I UV-blocking (senofilcon A) soft contact lens prevents UVA-induced yellow fluorescence and NADH loss in the rabbit lens nucleus in vivo”, Experimental eye research, Vol. 102, Elsevier Ltd, England, https://doi.org/10.1016/j.exer.2012.06.007
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
Lee, J. et al. (2004), “Reactive oxygen species, aging, and antioxidative nutraceuticals”, Comprehensive reviews in food science and food safety, Vol. 3/1, Blackwell Publishing Ltd, Oxford, https://doi.org/10.1111/j.1541-4337.2004.tb00058.x
Markkanen, E. (2017), “Not breathing is not an option: How to deal with oxidative DNA damage”, DNA repair, Vol. 59, Elsevier B.V., Netherlands, https://doi.org/10.1016/j.dnarep.2017.09.007
Mesa, R. and S. Bassnett (2013), “UV-B induced DNA damage and repair in the mouse lens”, Investigative ophthalmology & visual science, Vol. 54/10, the Association for Research in Vision and Ophthalmology, United States, https://doi.org/10.1167/iovs.13-12644
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, United States, pp. 1496-1513
Schoenfeld, M. P. et al. (2012), “A hypothesis on biological protection from space radiation through the use of new therapeutic gases as medical counter measures”, Medical gas research, Vol. 2/1, BioMed Central Ltd, India, https://doi.org/10.1186/2045-9912-2-8
Stohs, S. J. (1995), “The role of free radicals in toxicity and disease”, Journal of Basic and Clinical Physiology and Pharmacology, Vol. 6/3-4, https://doi.org/10.1515/JBCPP.1995.6.3-4.205
Wolf, N. et al. (2008), “Radiation cataracts: mechanisms involved in their long delayed occurrence but then rapid progression”, Molecular vision, Molecular Vision, United States, pp. 274-285
Zhang, Y. et al. (2010), “Oxygen-induced changes in mitochondrial DNA and DNA repair enzymes in aging rat lens”, Mechanisms of ageing and development, Vol. 131/11, Elsevier Ireland Ltd, Clare, https://doi.org/10.1016/j.mad.2010.09.003