API

Relationship: 1904

Title

?

Increase in RONS leads to Increase, DNA Damage

Upstream event

?

Increase in RONS

Downstream event

?


Increase, DNA Damage

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Adjacency Weight of Evidence Quantitative Understanding
Increased DNA damage leading to increased risk of breast cancer adjacent High Not Specified
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent High Not Specified

Taxonomic Applicability

?

Sex Applicability

?

Life Stage Applicability

?

Key Event Relationship Description

?


Increased RONS leads to an increase in DNA damage.

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.

 

Biological Plausibility

?

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).

Empirical Evidence

?

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.

Treatment with H2O2 or other RONS inducers increase DNA damage and double strand breaks. H2O2 treatment reaches the nucleus where it can damage DNA (Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015). Oxidized nucleotides (including clusters) and single strand breaks are commonly reported following H2O2 treatment (Dahm-Daphi, Sass et al. 2000; Nakamura, Purvis et al. 2003; Yang, Durando et al. 2013; Sharma, Collins et al. 2016), and double strand breaks can occur when transcription and translation machinery encounters damaged strands (Berdelle, Nikolova et al. 2011; Yang, Durando et al. 2013; Tubbs and Nussenzweig 2017). However, it is less clear whether H2O2 or RONS cause a measurable increase in double strand breaks, particularly at physiologically relevant concentrations (in the range of 12 uM) (Liu and Zweier 2001; Ameziane-El-Hassani, Talbot et al. 2015). Studies report double strand breaks following treatment with 15 uM- 1mM H2O2 (Oya, Yamamoto et al. 1986; Driessens, Versteyhe et al. 2009; Seager, Shah et al. 2012; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Sharma, Collins et al. 2016) as well as parallel increases in RONS and double strand breaks (Han, Chen et al. 2010; Berdelle, Nikolova et al. 2011; Stanicka, Russell et al. 2015). DNA damage including double strand breaks and mutations increase with H2O2 dose (Sandhu and Birnboim 1997; Dahm-Daphi, Sass et al. 2000; Driessens, Versteyhe et al. 2009; Seager, Shah et al. 2012; Lorat, Brunner et al. 2015; Sharma, Collins et al. 2016).

RONS is dose-dependently and reversibly associated with increased genomic instability (Dayal, Martin et al. 2008; Dayal, Martin et al. 2009; Buonanno, de Toledo et al. 2011; Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Bensimon, Biard et al. 2016) and with DNA damage in bystander cells (Azzam, De Toledo et al. 2002; Yang, Asaad et al. 2005; Yang, Anzenberg et al. 2007; Han, Chen et al. 2010; Buonanno, de Toledo et al. 2011) although other non-RONS factors such as telomere erosion and breakage-fusion-bridge events may be sufficient to maintain genomic instability (Suzuki, Kashino et al. 2009; Murnane 2012). To our knowledge no experiments have tested whether elevating intracellular RONS alone in one group of cells can cause DNA damage in nearby cells.

Antioxidants and other interventions to reduce RONS production also reduce or block the effect of RONS treatment on DNA base damage (Berdelle, Nikolova et al. 2011) and double-strand breaks (Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015; Stanicka, Russell et al. 2015). Similarly, nitric oxide scavengers can reduce DNA damage in cells treated with nitric oxide producers (Han, Chen et al. 2010) or in bystander cells.

Further support for a causative relationship between RONS and DNA damage comes from many studies showing that antioxidants and other interventions capable of reducing RONS can also reduce DNA damage following IR. Antioxidant reduction of nucleotide damage from IR occurs in isolated DNA (Winyard, Faux et al. 1992; Douki, Ravanat et al. 2006), and in vitro and in vivo antioxidants reduce nucleotide damage, double strand breaks, micronuclei, chromosomal damage, and mutations when added before (Azzam, De Toledo et al. 2002; Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Ameziane-El-Hassani, Boufraqech et al. 2010; Ozyurt, Cevik et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Fetisova, Antoschina et al. 2015; Manna, Das et al. 2015), or in the case of delayed (15 min to days) or bystander DNA damage, added after radiation (Yang, Asaad et al. 2005; Han, Chen et al. 2010; Pazhanisamy, Li et al. 2011; Ameziane-El-Hassani, Talbot et al. 2015). Interestingly, NO specific blockers reduce DNA damage and mutations in bystander cells but not in directly IR cells, suggesting that NO specifically contributes to the bystander effect (Zhou, Ivanov et al. 2008; Han, Chen et al. 2010).

Temporal concordance between RONS and DNA damage events following a stressor (ionizing radiation) is consistent with a causative relationship between RONS and DNA damage. Following ionizing radiation, an increase in RONS typically occurs coincident with DNA damage. Few studies examine multiple doses and time points, and detection methods have differing sensitivities. However, both RONS and double strand breaks appear rapidly after IR (Ameziane-El-Hassani, Boufraqech et al. 2010; Denissova, Nasello et al. 2012; Martin, Nakamura et al. 2014), and in several studies RONS and DNA single and double strand breaks, chromosomal damage, and micronuclei appear at the same time points over several days following IR (Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Du, Gao et al. 2009; Saenko, Cieslar-Pobuda et al. 2013; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015). RONS also appears coincident with longer term DNA damage including nucleotide damage, double strand breaks, and micronuclei, both in IR exposed (Dayal, Martin et al. 2008; Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015) and in bystander cells not directly exposed to IR (Buonanno, de Toledo et al. 2011).

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).

Quantitative Understanding of the Linkage

?


Response-response Relationship

?

Time-scale

?

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).

 

Barcellos-Hoff, M. H. and T. A. Dix (1996). "Redox-mediated activation of latent transforming growth factor-beta 1." Mol Endocrinol 10(9): 1077-1083.

Blaser, H., C. Dostert, et al. (2016). "TNF and ROS Crosstalk in Inflammation." Trends in cell biology 26(4): 249-261.

Cavaillon, J.-M. (2018). Damage-associated Molecular Patterns. Inflammation: From Molecular and Cellular Mechanisms to the Clinic. J.-M. Cavaillon and M. Singer, Wiley-VCHVerlagGmbH&Co.KGaA.: 57-80.

Gloire, G., S. Legrand-Poels, et al. (2006). "NF-kappaB activation by reactive oxygen species: fifteen years later." Biochem Pharmacol 72(11): 1493-1505.

Jobling, M. F., J. D. Mott, et al. (2006). "Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species." Radiation research 166(6): 839-848.

Matsuzawa, A., K. Saegusa, et al. (2005). "ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity." Nat Immunol 6(6): 587-592.

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.

Morgan, M. J. and Z. G. Liu (2011). "Crosstalk of reactive oxygen species and NF-kappaB signaling." Cell Res 21(1): 103-115.

Nakahira, K., H. P. Kim, et al. (2006). "Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts." J Exp Med 203(10): 2377-2389.

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.

Powers, K. A., K. Szaszi, et al. (2006). "Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages." J Exp Med 203(8): 1951-1961.

Ratikan, J. A., E. D. Micewicz, et al. (2015). "Radiation takes its Toll." Cancer Lett 368(2): 238-245.

Zhao, W. and M. E. Robbins (2009). "Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications." Curr Med Chem 16(2): 130-143.

Domain of Applicability

?


References

?


Ameziane-El-Hassani, R., M. Boufraqech, et al. (2010). "Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells." Cancer Res 70(10): 4123-4132.

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.

Aziz, K., S. Nowsheen, et al. (2012). "Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy." Pharmacology & therapeutics 133(3): 334-350.

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.

Cadet, J., K. J. A. Davies, et al. (2017). "Formation and repair of oxidatively generated damage in cellular DNA." Free radical biology & medicine 107: 13-34.

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.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.

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.

Dickinson, B. C. and C. J. Chang (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511.

Douki, T., J. L. Ravanat, et al. (2006). "Minor contribution of direct ionization to DNA base damage inducedby heavy ions." International journal of radiation biology 82(2): 119-127.

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.

Du, C., Z. Gao, et al. (2009). "Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts." Cancer Biol Ther 8(20): 1962-1971.

Fetisova, E. K., M. M. Antoschina, et al. (2015). "Radioprotective effects of mitochondria-targeted antioxidant SkQR1." Radiation research 183(1): 64-71.

Gradzka, I. and T. Iwanenko (2005). "A non-radioactive, PFGE-based assay for low levels of DNA double-strand breaks in mammalian cells." DNA repair 4(10): 1129-1139.

Han, W., S. Chen, et al. (2010). "Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation." Mutation research 684(1-2): 81-89.

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.

Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.

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.

Martin, N. T., K. Nakamura, et al. (2014). "Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks." Cell Death Dis 5: e1130.

Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.

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.

Ozyurt, H., O. Cevik, et al. (2014). "Quercetin protects radiation-induced DNA damage and apoptosis in kidney and bladder tissues of rats." Free Radic Res 48(10): 1247-1255.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

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.

Sandhu, J. K. and H. C. Birnboim (1997). "Mutagenicity and cytotoxicity of reactive oxygen and nitrogen species in the MN-11 murine tumor cell line." Mutation research 379(2): 241-252.

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.

Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.

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.

Suzuki, K., G. Kashino, et al. (2009). "Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells." Mutation research 671(1-2): 33-39.

Tubbs, A. and A. Nussenzweig (2017). "Endogenous DNA Damage as a Source of Genomic Instability in Cancer." Cell 168(4): 644-656.

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.

Yang, H., V. Anzenberg, et al. (2007). "The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts." Radiation research 168(3): 292-298.

Yang, H., N. Asaad, et al. (2005). "Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts." Oncogene 24(12): 2096-2103.

Yang, Y., M. Durando, et al. (2013). "Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage." Nucleic acids research 41(4): 2296-2312.

Yoshida, T., S. Goto, et al. (2012). "Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation." Free Radic Res 46(2): 147-153.

Zhou, H., V. N. Ivanov, et al. (2008). "Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects." Cancer Res 68(7): 2233-2240.