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Increase, Oxidative DNA damage leads to Increase, DNA strand breaks
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Oxidative DNA damage leading to chromosomal aberrations and mutations||non-adjacent||Moderate||Low||Carole Yauk (send email)||Open for comment. Do not cite||WPHA/WNT Endorsed|
|Deposition of energy leading to occurrence of cataracts||adjacent||Low||Low||Vinita Chauhan (send email)||Open for citation & comment|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
The repair of oxidative DNA lesions produced by exposure to reactive oxygen species (ROS) involves excision repair, where damaged base is removed by glycosylases, a strand break is generated 5’ to the apurinic/apyrimidinic (AP) site by lyases and endonucleases, and finally, a new strand is synthesized across the break. Although these strand breaks are mostly transient under normal conditions, elevated levels of oxidative DNA lesions can increase the early AP lyase activities generating a higher number of SSBs that can be more persistent (Yang et al., 2004; Yang et al., 2006). These SSBs can exacerbate the DNA damage by interfering with the replication fork causing it to collapse, and ultimately becoming double strand breaks (DSBs).
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: Low
The mechanism of repair of oxidative DNA damage in humans is well-established and numerous literature reviews are available on this topic (Berquist and Wilson III, 2012; Cadet and Wagner, 2013). Oxidative DNA damage is mostly repaired via base excision repair (BER) and via nucleotide excision repair (NER) to a lesser extent. With an increase in oxidative DNA lesions, the more glycosylase and lyase activities occur, introducing SSBs at a higher rate than at homeostasis. It is highly plausible that an increase in SSBs also increases the risk for DSBs, which are more difficult to repair accurately. Previous studies have reported thresholded dose-response curves in oxidative DNA damage and attributed these observations to failed repair at the inflection point on the curve, thus allowing strand breaks to accumulate (Gagne et al., 2012; Seager et al., 2012). When DNA bases sustain oxidative damage via ROS through base oxidation or deletion, this creates small nicks in the DNA strand (Cannan & Pederson, 2016). The bases guanine and adenine are most vulnerable to oxidative damage due to their low oxidation potentials (Fong, 2016). The mechanism of repair, BER, will work to fix these SSBs. If there are multiple SSBs close together in space and time, there will be many sites of BER occurring close together that can cause strain on the strand and result in the conversion of the SSBs to DSBs prior to completion of repair (Cannan & Pederson, 2016).
Uncertainties and Inconsistencies
As demonstrated by the Domijan et al paper, results can be complicated by mixed MOA’s. The comet results were positive with and without Fpg suggesting oxidative stress is not the only mechanism.
Known modulating factors
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 male rats and human male adolescent in vitro models.
Berdelle, N., Nikolova, T., Quiros, S., Efferth, T., Kaina, B. (2011), Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM/ATR Damage Response in Cancer Cells, Mol Cancer Ther, 10:2224-2233.
Berquist, B., Wilson III, D. (2012), Pathways for Repairing and Tolerating the Spectrum of Oxidative DNA Lesions, Cancer Lett, 327:61-72.
Bouaicha, N., Maatouk, I. (2004), Microcystin-LR and nodularin induce intracellular glutathione alteration, reactive oxygene species production and lipid peroxidation in primary cultured rat hepatocytes, Toxicol Lett, 148:53-63.
Cadet, J., Wagner, J.R. (2013), DNA Base Damage by Reactive Oxygen Species, Oxidizing Agents, and UV Radiation, Cold Spring Harb Perspect Biol, 5:a012559.
Cannan, W. and D. Pederson. (2016), “Mechanisms and consequences of double-strand DNA break formation in chromatin”, Journal of Cell Physiology, Vol.231/1, Wiley, Hoboken, https://doi.org/10.1002/jcp.25048.
Deferme, L., Briede, J.J., Claessen, S.M., Jennen, D.G., Cavill, R., Kleinjans, J.C. (2013), Time series analysis of oxidative stress response patterns in HepG2: A toxicogenomics approach , Toxicol, 306:24-34.
Domijan, A., Zeljezic, D., Kopjar, D., Peraica, M. (2006), Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and fumonisin B(1)-treated rats, Toxciol, 222:53-59.
Fong, C.W. (2016), “Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect”, Free Radical Biology and Medicine, Vol.95/June 2016, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2016.03.006.
Gagne, J., Rouleau, M., Poirier, G. (2012), PARP-1 Activation— Bringing the Pieces Together, Science, 336:678-279.
Jin, L., Yang, H., Fu, J., Xue, X., Yao, L., Qiao, L. (2015), Association between oxidative DNA damage and the expression of 8-oxoguanine DNA glycosylase 1 in lung epithelial cells of neonatal rats exposed to hyperoxia, Mol Med Rep, 11: 4079-4086.
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
Lankoff, A., Wojcik, A., Fessard, V., Meriluoto, J. (2006), Nodularin-induced genotoxicity following oxidative DNA damage and aneuploidy in HepG2 cells, Toxicol Lett, 164:239-248.
Seager, A., Shah, U., Mikhail, J., Nelson, B., Marquis, B., Doak, S., Johnson, G., Griffiths, S., Carmichael, P., Scott, S., Scott, A., Jenkins, G. (2012), Pro-oxidant Induced DNA Damage in Human Lymphoblastoid Cells: Homeostatic Mechanisms of Genotoxic Tolerance, Toxicol Sci, 128:387-397.
Spassova, M., Miller, D., Nikolov, A. (2015), Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage, Oxid Med Cell Longev, 2015:764375.
Yang, N., Chaudry, A., Wallace, S. (2006), Base excision repair by hNTH1 and hOGG1: A two edged sword in the processing of DNA damage in gamma-irradiated human cells, DNA Repair, 5:43-51.
Yang, N., Galick, H., Wallace, S. (2004), Attempted base excision repair of ionizing radiation damage in human lymphoblastoid cells produces lethal and mutagenic double strand breaks, DNA Repair, 3:1323-1334.