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Relationship: 1904
Title
Increase in RONS leads to Increase, DNA Damage
Upstream event
Downstream event
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 | Allie Always (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 Do not cite | Under Development |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 | Evgeniia Kazymova (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 Do not cite | Under Development |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 | Allie Always (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Increased RONS leads to an increase in DNA damage.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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).
Response-response Relationship
Time-scale
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).