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Relationship: 1906


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase in RONS leads to Tissue resident cell activation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent Moderate Not Specified Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite Under Development
Increased DNA damage leading to increased risk of breast cancer adjacent Moderate Not Specified Allie Always (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Increased RONS leads to an increase in inflammation.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility is Moderate. RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-β, NF-kB), and RONS are an essential part of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF-a, TGF-β, NF-kB).

Empirical Evidence is Moderate. Both RONS and inflammation increase in response to agents that increase RONS or inflammation, and antioxidants reduce inflammation. Multiple studies show dose-dependent changes in both RONS and inflammation in response to stressors including ionizing radiation and antioxidants. RONS have been measured at the same or earlier time points as inflammatory markers, but additional studies are needed to characterize the inflammatory response at the earliest time points to support causation. Uncertainties come from the positive feedback from inflammation to RONS potentially interfering with attempts to establish causality, and from the large number of inflammation-related endpoints with differing responses to stressors and experimental variation.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Biological Plausibility is   Moderate. RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-β, NF-kB), and RONS are an essential part of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF-a, TGF-β, NF-kB).

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).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Although ROS can activate NF-KB (Gloire, Legrand-Poels et al. 2006), not all studies consistently show NF-kB activation after RONS stressor IR. It is possible that the link between ROS and NF-kB depends on the local environmental context, with different studies not adequately controlling all influential variables. One study offers a possible explanation based on temporal response: in macrophages, NF-kB was activated by shorter exposures to H2O2 (30 min), but the response disappeared with longer exposures (Nakao, Kurokawa et al. 2008).

While many models in vivo and in vitro showed a decreased inflammatory response to RONS stressors IR in combination with antioxidants, in endothelial cells in culture the increase in IL6 and IL8 after IR was not reduced by antioxidants, although a synergistic increase in those cytokines occurring with combined TNF-a and IR treatment was reduced by antioxidants (Meeren, Bertho et al. 1997). This is a reminder that multiple mechanisms can increase inflammation, that inflammatory factors participate in positive feedback loops, and that responses to stimuli vary between cells.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

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.

Azimzadeh, O., H. Scherthan, et al. (2011). "Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation." Proteomics 11(16): 3299-3311.

Azimzadeh, O., W. Sievert, et al. (2015). "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction." J Proteome Res 14(2): 1203-1219.

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.

Berruyer, C., F. M. Martin, et al. (2004). "Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress." Mol Cell Biol 24(16): 7214-7224.

Black, A. T., M. K. Gordon, et al. (2011). "UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells." Biochem Pharmacol 81(7): 873-880.

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.

Das, U., K. Manna, et al. (2014). "Role of ferulic acid in the amelioration of ionizing radiation induced inflammation: a murine model." PLoS One 9(5): e97599.

Ezz, M. K., N. K. Ibrahim, et al. (2018). "The Beneficial Radioprotective Effect of Tomato Seed Oil Against Gamma Radiation-Induced Damage in Male Rats." J Diet Suppl 15(6): 923-938.

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

Ha, Y. M., S. W. Chung, et al. (2010). "Molecular activation of NF-kappaB, pro-inflammatory mediators, and signal pathways in gamma-irradiated mice." Biotechnol Lett 32(3): 373-378.

Haddadi, G. H., A. Rezaeyan, et al. (2017). "Hesperidin as Radioprotector against Radiation-induced Lung Damage in Rat: A Histopathological Study." J Med Phys 42(1): 25-32.

Han, S. J., H. J. Min, et al. (2015). "HMGB1 in the pathogenesis of ultraviolet-induced ocular surface inflammation." Cell Death Dis 6: e1863.

Hiramoto, K., H. Kobayashi, et al. (2012). "Intercellular pathway through hyaluronic acid in UVB-induced inflammation." Exp Dermatol 21(12): 911-914.

Hung, S. J., S. C. Tang, et al. (2017). "Photoprotective Potential of Glycolic Acid by Reducing NLRC4 and AIM2 Inflammasome Complex Proteins in UVB Radiation-Induced Normal Human Epidermal Keratinocytes and Mice." DNA Cell Biol 36(2): 177-187.

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.

Kang, J. S., H. N. Kim, et al. (2007). "Regulation of UVB-induced IL-8 and MCP-1 production in skin keratinocytes by increasing vitamin C uptake via the redistribution of SVCT-1 from the cytosol to the membrane." J Invest Dermatol 127(3): 698-706.

Khan, A., K. Manna, et al. (2015). "Gossypetin ameliorates ionizing radiation-induced oxidative stress in mice liver--a molecular approach." Free Radic Res 49(10): 1173-1186.

Lee, E. J., M. S. Jeon, et al. (2010). "Capsiate inhibits ultraviolet B-induced skin inflammation by inhibiting Src family kinases and epidermal growth factor receptor signaling." Free radical biology & medicine 48(9): 1133-1143.

Lee, S. J., A. Dimtchev, et al. (1998). "A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB." Oncogene 17(14): 1821-1826.

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, K., R. Sur, et al. (2008). "Parthenolide-depleted Feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression." Arch Dermatol Res 300(2): 69-80.

Martinez, R. M., F. A. Pinho-Ribeiro, et al. (2016). "Topical formulation containing hesperidin methyl chalcone inhibits skin oxidative stress and inflammation induced by ultraviolet B irradiation." Photochem Photobiol Sci 15(4): 554-563.

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.

Meeren, A. V., J. M. Bertho, et al. (1997). "Ionizing radiation enhances IL-6 and IL-8 production by human endothelial cells." Mediators Inflamm 6(3): 185-193.

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.

Nakao, N., T. Kurokawa, et al. (2008). "Hydrogen peroxide induces the production of tumor necrosis factor-alpha in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase." Innate Immun 14(3): 190-196.

Narayanan, P. K., K. E. LaRue, et al. (1999). "Alpha particles induce the production of interleukin-8 by human cells." Radiation research 152(1): 57-63.

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.

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.

Park, L. J., S. M. Ju, et al. (2006). "The enhanced monocyte adhesiveness after UVB exposure requires ROS and NF-kappaB signaling in human keratinocyte." J Biochem Mol Biol 39(5): 618-625.

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.

Ren, X., Y. Shi, et al. (2016). "Naringin protects ultraviolet B-induced skin damage by regulating p38 MAPK signal pathway." J Dermatol Sci 82(2): 106-114.

Saltman, B., D. H. Kraus, et al. (2010). "In vivo and in vitro models of ionizing radiation to the vocal folds." Head Neck 32(5): 572-577.

Sharma, S. D., S. M. Meeran, et al. (2007). "Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling in in vivo SKH-1 hairless mice." Molecular cancer therapeutics 6(3): 995-1005.

Sinha, M., D. K. Das, et al. (2011). "Leaf extract of Moringa oleifera prevents ionizing radiation-induced oxidative stress in mice." J Med Food 14(10): 1167-1172.

Sinha, M., D. K. Das, et al. (2012). "Epicatechin ameliorates ionising radiation-induced oxidative stress in mouse liver." Free Radic Res 46(7): 842-849.

Soltani, B., N. Ghaemi, et al. (2016). "Redox maintenance and concerted modulation of gene expression and signaling pathways by a nanoformulation of curcumin protects peripheral blood mononuclear cells against gamma radiation." Chem Biol Interact 257: 81-93.

Straub, J. M., J. New, et al. (2015). "Radiation-induced fibrosis: mechanisms and implications for therapy." J Cancer Res Clin Oncol 141(11): 1985-1994.

Zetner, D., L. P. Andersen, et al. (2016). "Melatonin as Protection Against Radiation Injury: A Systematic Review." Drug Res (Stuttg) 66(6): 281-296.

Zhang, Q., L. Zhu, et al. (2017). "Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS." J Biochem Mol Toxicol 31(3).

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.