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Frustrated phagocytosis leads to malignant mesothelioma
Point of Contact
- Nureddin Mansour
- Penny Nymark
- Merlin Mei
- Evgeniia Kazymova
|Handbook Version||OECD status||OECD project|
This AOP was last modified on April 29, 2023 13:02
|Frustrated phagocytosis||September 16, 2022 09:03|
|Increased, secretion of proinflammatory mediators||April 21, 2023 09:51|
|Increased, recruitment of inflammatory cells||April 25, 2023 11:33|
|Increased, Reactive oxygen species||April 10, 2023 14:01|
|Increased, DNA damage and mutation||August 13, 2019 05:41|
|Genomic instability||July 06, 2021 06:05|
|Increase, Cell Proliferation||April 24, 2023 11:08|
|Increased, mesotheliomas||December 03, 2016 16:37|
|Frustrated phagocytosis leads to Increased proinflammatory mediators||July 06, 2021 06:10|
|Frustrated phagocytosis leads to Increased, Reactive oxygen species||July 06, 2021 06:11|
|Increased proinflammatory mediators leads to Recruitment of inflammatory cells||April 25, 2023 14:01|
|Recruitment of inflammatory cells leads to Increased, Reactive oxygen species||July 03, 2019 11:53|
|Increased, Reactive oxygen species leads to Increased, DNA damage and mutation||July 03, 2019 11:53|
|Increased, DNA damage and mutation leads to Genomic instability||July 06, 2021 06:12|
|Genomic instability leads to Increase, Cell Proliferation||July 06, 2021 06:12|
|Increase, Cell Proliferation leads to Increased, mesotheliomas||July 06, 2021 06:13|
|Multi-walled carbon nanotubes||July 26, 2017 18:59|
|Asbestos fibers||September 02, 2021 09:31|
|High aspect ratio material||August 13, 2019 04:38|
|Carbon nanotubes||August 09, 2017 08:03|
|Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres||January 01, 2018 17:52|
|Single walled carbon nanotubes||July 26, 2017 18:58|
This AOP starts with frustrated phagocytosis, meaning that macrophages fail to engulf long fibers and die with a concomitant massive release of ROS and pro-inflammatory signals. Any fibre that exceeds a maximum length for macrophage uptake will result in frustrated phagocytosis. The release of ROS and pro-inflammatory signals together with persistent cytotoxicity and tissue injury in the pleura can lead to secondary genotoxicity, including oxidative lesions to DNA. When DNA repair pathways are overwhelmed and the DNA lesions exceed the repair capacity, it may lead to mutagenesis with increased mutations and DNA double strand breaks. Increased DNA damage increases the risk for genomic instability and accumulation of mutations in mesothelial cells. Specific mutations and chromosomal aberrations have been associated with mesothelioma, including for example mutation of BAP1 and other genes, and loss of chromosomal regions 3p21 (which harbours the BAP1 gene) and 9p21. These mutations and deletions are assumed to be involved in the molecular and genetic alterations that drive mesothelial cell proliferation, which is the final key event leading to the adverse outcome: malignant pleural mesothelioma.
There is abundant evidence for this process taking place in humans exposed to asbestos fibres. Recently, experimental evidence from both in vivo and in vitro studies indicate that a similar process may take place in humans exposed to cetrain types of nanomaterials with high aspect ratios, such as multi-walled carbon nanotubes.
AOP Development Strategy
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||1668||Frustrated phagocytosis||Frustrated phagocytosis|
|KE||1496||Increased, secretion of proinflammatory mediators||Increased proinflammatory mediators|
|KE||1497||Increased, recruitment of inflammatory cells||Recruitment of inflammatory cells|
|KE||1115||Increased, Reactive oxygen species||Increased, Reactive oxygen species|
|KE||1669||Increased, DNA damage and mutation||Increased, DNA damage and mutation|
|KE||1896||Genomic instability||Genomic instability|
|KE||870||Increase, Cell Proliferation||Increase, Cell Proliferation|
|AO||1090||Increased, mesotheliomas||Increased, mesotheliomas|
Relationships Between Two Key Events (Including MIEs and AOs)
|Frustrated phagocytosis leads to Increased proinflammatory mediators||adjacent||High||Not Specified|
|Increased proinflammatory mediators leads to Recruitment of inflammatory cells||adjacent||High||Not Specified|
|Recruitment of inflammatory cells leads to Increased, Reactive oxygen species||adjacent||High||Not Specified|
|Increased, Reactive oxygen species leads to Increased, DNA damage and mutation||adjacent||High||Not Specified|
|Increased, DNA damage and mutation leads to Genomic instability||adjacent||High||Not Specified|
|Genomic instability leads to Increase, Cell Proliferation||adjacent||Not Specified||Not Specified|
|Increase, Cell Proliferation leads to Increased, mesotheliomas||adjacent||High||Not Specified|
|Frustrated phagocytosis leads to Increased, Reactive oxygen species||non-adjacent||High||Not Specified|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
Considerations for Potential Applications of the AOP (optional)
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