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Key Event Title
Increased, DNA damage and mutation
|Level of Biological Organization|
Key Event Components
|DNA damage response, detection of DNA damage||site of DNA damage||increased|
|abnormal DNA repair||DNA repair complex||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Frustrated phagocytosis-induced lung cancer||KeyEvent||Carole Seidel (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Frustrated phagocytosis leads to malignant mesothelioma||KeyEvent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
|AHR activation leading to lung cancer via IL-6 tox path||KeyEvent||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
|AHR activation leading to lung cancer via AHR-ARNT tox path||KeyEvent||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
|DNA damage and metastatic breast cancer||MolecularInitiatingEvent||Usha Adiga (send email)||Under development: Not open for comment. Do not cite|
|Interaction with lung cells leads to lung cancer||KeyEvent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
DNA damages are alteration of the DNA backbone including abasic site, single or double strand breaks or inter-strand crosslinks. These damages could be recognized and repaired by specialized enzymes. However, if damages persist, mutation in the DNA sequences can occur. Unlike DNA damages, DNA mutations when both strands are modified cannot be repaired and are heritable. Mutations affect the genotype and could affect phenotype.
Different mechanisms are implicated in DNA damage such as oxidative burst, DNA repair dysfunction or centrosome amplification and chromosome instability .
How It Is Measured or Detected
DNA damages could be measured using different assays, such as micronucleus formation (OECD n°487) , comet assay with different protocols for the detection of double and single-strand breaks, DNA-DNA and DNA-protein crosslinks, adduct and oxidized nucleotides (OECD n°489) [3, 4] and γH2AX for the analysis of DNA strand breaks .
DNA mutation could be analyzed with Ames test or via the analysis of frequencies of mutations (OECD n°471) .
Domain of Applicability
The DNA damages and mutations can occur in mammals, male or female, and is generally measured in adults.
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
1. Zhang Y. Cell toxicity mechanism and biomarker. 2018;7 1:34; doi: 10.1186/s40169-018-0212-7.
2. Kato T, Totsuka Y, Ishino K, Matsumoto Y, Tada Y, Nakae D, et al. Genotoxicity of multi-walled carbon nanotubes in both in vitro and in vivo assay systems. Nanotoxicology. 2013;7 4:452-61; doi: 10.3109/17435390.2012.674571.
3. Pacurari M, Yin XJ, Zhao J, Ding M, Leonard SS, Schwegler-Berry D, et al. Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells. 2008;116 9:1211-7; doi: 10.1289/ehp.10924.
4. Hiraku Y, Guo F, Ma N, Yamada T, Wang S, Kawanishi S, et al. Multi-walled carbon nanotube induces nitrative DNA damage in human lung epithelial cells via HMGB1-RAGE interaction and Toll-like receptor 9 activation. Particle and fibre toxicology. 2016;13:16; doi: 10.1186/s12989-016-0127-7.
5. Catalan J, Siivola KM, Nymark P, Lindberg H, Suhonen S, Jarventaus H, et al. In vitro and in vivo genotoxic effects of straight versus tangled multi-walled carbon nanotubes. Nanotoxicology. 2016;10 6:794-806; doi: 10.3109/17435390.2015.1132345.
6. Fukai E, Sato H, Watanabe M, Nakae D, Totsuka Y. Establishment of an in vivo simulating co-culture assay platform for genotoxicity of multi-walled carbon nanotubes. Cancer science. 2018; doi: 10.1111/cas.13534.