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Increase in RONS leads to Increase, DNA Damage
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||High||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||High||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability||adjacent||Moderate||Moderate||Deborah Oughton (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Increased RONS leads to an increase in DNA damage.
Evidence Collection Strategy
Evidence Supporting this KER
Biological plausibiltiy is High. Reactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under a range of cellular conditions.
Empirical support is High. Multiple studies show an increase in DNA damage with RONS treatment as well as dependent changes in both RONS and DNA damage in response to stressors. DNA damage increases with RONS dose, and temporal concordance between RONS and DNA damage events following ionizing radiation is consistent with a causative relationship, although few studies examine multiple doses and time points. A small number of studies do not find double strand breaks at physiological doses, or report an increase in one key event but not the other.
High. Reactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under typical cellular conditions (Dickinson and Chang 2011; Aziz, Nowsheen et al. 2012; Tubbs and Nussenzweig 2017). Damage commonly occurs via oxidation of a nucleotide by the hydroxyl radical (or by radicals created by nitric oxide), or can occur indirectly in nearby nucleotides following the secondary reaction of a radical created in nucleotides (Cadet, Davies et al. 2017). Oxidative damage predominantly consists of DNA lesions (structural modifications to nucleotides) including single strand breaks, although double strand breaks can occur when transcription or translation machinery encounters damaged strands (Tubbs and Nussenzweig 2017).
Uncertainties and Inconsistencies
While the bulk of the evidence support a mechanism where RONS increases DNA damage, including double strand DNA breaks, not all studies report these effects. Some studies report the induction of single strand breaks by H2O2, but only show double strand breaks with H2O2 doses at or above 1 mM H2O2 (Dahm-Daphi, Sass et al. 2000; Lorat, Brunner et al. 2015) or do not find an effect of H2O2 on double strand breaks at any concentration (Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005). These conflicting results may be partially explained by experimental variations including temperature (two of the studies showing reduced or no effect were exposed to H2O2 at 4C or colder) or other factors including catalysts required to transform H2O2 into DNA damaging OH radicals (Nakamura, Purvis et al. 2003). The reduction of IR-induced DNA damage (including double strand breaks) by antioxidants is strong evidence for an essential role of RONS in DNA damage, but antioxidants don’t reduce all DNA damage from IR and anti-oxidants that reduce double strand breaks and chromosomal aberrations after IR don’t necessarily reduce baseline DNA damage (Fetisova, Antoschina et al. 2015). This incomplete effect suggests either that antioxidants are unable to fully reduce endogenous RONS, or that additional sources of DNA damage are also at work. Furthermore, RONS can be observed following IR in the absence of DNA nucleotide damage (Yoshida, Goto et al. 2012) and counter to expectations lower (10 uM) doses of H2O2 applied six days after IR were associated with a decrease in detectable micronuclei (Werner, Wang et al. 2014), suggesting that additional factors (such as repair and apoptosis or changes in endogenous antioxidants) may influence the effect of RONS on IR-induced DNA damage. Finally, double strand breaks and chromosomal damage can be observed following IR in the absence of measured RONS (Suzuki, Kashino et al. 2009), although since antioxidants are still capable of reducing DNA damage in the absence of measurable RONS, such a discrepancy might be attributable to a lack of sensitivity in RONS detection methods (Yang, Asaad et al. 2005).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
RONS activates or is essential to many inflammatory pathways including TGF-β (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB. Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016).
Damage inflicted by RONS on cells activate TLRs and other receptors to promote release of cytokines (Ratikan, Micewicz et al. 2015). For example, oxidized lipids or oxidative stress-induced heat shock proteins can activate TLR4 (Miller, Goodson et al. 2017; Cavaillon 2018).
ROS is essential to TLR4 activation of downstream signals including NF-kB. Activation of TLR4 promotes the surface expression and movement of TLR4 into signal-promoting lipid rafts (Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). This signal promotion requires NADPH-oxidase and ROS (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). ROS is also required for the TLR4/TRAF6/ASK-1/p38 dependent activation of inflammatory cytokines (Matsuzawa, Saegusa et al. 2005). ROS therefore amplifies the inflammatory process.
RONS can also fail to activate or actively inhibit inflammatory pathways, and the circumstances determining response to RONS are not well known (Gloire, Legrand-Poels et al. 2006).
Miller, M. F., W. H. Goodson, et al. (2017). "Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: Scientific Underpinnings and Research Recommendations." Environmental health perspectives 125(2): 163-169.
Park, H. S., H. Y. Jung, et al. (2004). "Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B." J Immunol 173(6): 3589-3593.
Domain of Applicability
Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.
Azzam, E. I., S. M. De Toledo, et al. (2002). "Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures." Cancer research 62(19): 5436-5442.
Bensimon, J., D. Biard, et al. (2016). "Forced extinction of CD24 stem-like breast cancer marker alone promotes radiation resistance through the control of oxidative stress." Mol Carcinog 55(3): 245-254.
Berdelle, N., T. Nikolova, et al. (2011). "Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells." Molecular cancer therapeutics 10(12): 2224-2233.
Buonanno, M., S. M. de Toledo, et al. (2011). "Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress." Radiation research 175(4): 405-415.
Choi, K. M., C. M. Kang, et al. (2007). "Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK." Oncol Rep 17(5): 1183-1188.
Dahm-Daphi, J., C. Sass, et al. (2000). "Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells." International journal of radiation biology 76(1): 67-75.
Dayal, D., S. M. Martin, et al. (2009). "Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation." Radiation research 172(6): 737-745.
Denissova, N. G., C. M. Nasello, et al. (2012). "Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage." Carcinogenesis 33(1): 149-155.
Driessens, N., S. Versteyhe, et al. (2009). "Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ." Endocrine-related cancer 16(3): 845-856.
Ismail, I. H., S. Nystrom, et al. (2005). "Activation of ataxia telangiectasia mutated by DNA strand break-inducing agents correlates closely with the number of DNA double strand breaks." J Biol Chem 280(6): 4649-4655.
Liu, X. and J. L. Zweier (2001). "A real-time electrochemical technique for measurement of cellular hydrogen peroxide generation and consumption: evaluation in human polymorphonuclear leukocytes." Free radical biology & medicine 31(7): 894-901.
Lorat, Y., C. U. Brunner, et al. (2015). "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair." DNA repair 28: 93-106.
Manna, K., U. Das, et al. (2015). "Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes." Free Radic Res 49(4): 422-439.
Nakamura, J., E. R. Purvis, et al. (2003). "Micromolar concentrations of hydrogen peroxide induce oxidative DNA lesions more efficiently than millimolar concentrations in mammalian cells." Nucleic acids research 31(6): 1790-1795.
Oya, Y., K. Yamamoto, et al. (1986). "The biological activity of hydrogen peroxide. I. Induction of chromosome-type aberrations susceptible to inhibition by scavengers of hydroxyl radicals in human embryonic fibroblasts." Mutation research 172(3): 245-253.
Saenko, Y., A. Cieslar-Pobuda, et al. (2013). "Changes of reactive oxygen and nitrogen species and mitochondrial functioning in human K562 and HL60 cells exposed to ionizing radiation." Radiation research 180(4): 360-366.
Seager, A. L., U. K. Shah, et al. (2012). "Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance." Toxicological sciences : an official journal of the Society of Toxicology 128(2): 387-397.
Stanicka, J., E. G. Russell, et al. (2015). "NADPH oxidase-generated hydrogen peroxide induces DNA damage in mutant FLT3-expressing leukemia cells." The Journal of biological chemistry 290(15): 9348-9361.
Werner, E., H. Wang, et al. (2014). "Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability." PLoS One 9(10): e108234.
Winyard, P. G., S. P. Faux, et al. (1992). "Bleomycin-induced unscheduled DNA synthesis in non-permeabilized human and rat hepatocytes is not paralleled by 8-oxo-7,8-dihydrodeoxyguanosine formation." Biochem Pharmacol 44(7): 1255-1260.