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Leukocyte recruitment/activation leads to Increase in RONS
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||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 Do not cite||Under Development|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 Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Leukocyte recruitment and activation increases reactive oxygen and nitrogen species (RONS).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells
Empirical Support is High. Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and the stressor ionizing radiation (IR) increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.
Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Inflammation-related signals contributing to RONS include the cytokines TNF-a, IL1, and INF and the JNK/MAPK pathway (Bubici, Papa et al. 2006; Yang, Elner et al. 2007; Blaser, Dostert et al. 2016), as well as neutrophil and macrophage immune cells (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992; Fan, Li et al. 2007; Lorimore, Chrystal et al. 2008; Rastogi, Boylan et al. 2013; Weigert, von Knethen et al. 2018).
Uncertainties and Inconsistencies
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.
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.
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.
Lorimore, S. A., J. A. Chrystal, et al. (2008). "Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation." Cancer Res 68(19): 8122-8126.
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.
Natarajan, M., C. F. Gibbons, et al. (2007). "Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells." Br J Radiol 80 Spec No 1: S13-22.
Redon, C. E., J. S. Dickey, et al. (2010). "Tumors induce complex DNA damage in distant proliferative tissues in vivo." Proceedings of the National Academy of Sciences of the United States of America 107(42): 17992-17997.
Shibata, W., S. Takaishi, et al. (2010). "Conditional deletion of IkappaB-kinase-beta accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia." Gastroenterology 138(3): 1022-1034 e1021-1010.
Stevens, C. R., N. Bucurenci, et al. (1992). "Application of methionine as a detector molecule for the assessment of oxygen radical generation by human neutrophils and endothelial cells." Free Radic Res Commun 17(2): 143-154.
Zhou, H., V. N. Ivanov, et al. (2005). "Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway." Proceedings of the National Academy of Sciences of the United States of America 102(41): 14641-14646.