This AOP is licensed under a Creative Commons Attribution 4.0 International License.
AOP for urothelial carcinogenesis due to chemical cytotoxicity by mitochondrial impairment
- Nathalia Pereira Souza
- Thania Rios Rossi Lima
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on April 21, 2020 19:41
|Mitochondrial impairment||September 16, 2017 10:17|
|Urothelial cell injury/death||April 21, 2020 18:09|
|Increase, Regenerative cell proliferation (urothelial cells)||September 16, 2017 10:16|
|Increase, Hyperplasia (urothelial)||September 16, 2017 10:16|
|Urothelial Tumor||April 21, 2020 19:38|
|Mitochondrial impairment leads to cell injury||April 21, 2020 18:42|
|cell injury leads to Increase, Regenerative cell proliferation (urothelial cells)||April 21, 2020 18:42|
|Increase, Regenerative cell proliferation (urothelial cells) leads to Increase, Hyperplasia (urothelial)||December 03, 2016 16:38|
|Increase, Hyperplasia (urothelial) leads to carcinogenicity||April 21, 2020 18:43|
|Diuron||May 24, 2018 15:29|
We are proposing an AOP framework for urothelial cytotoxicity followed by regenerative hyperplasia and the development of benign and malignant proliferative lesions after long-term chemical exposure. In addition, we suggest direct mitochondrial dysfunction process as one of the possible Molecular Initiating Event (MIE) for this AOP. Our lab has a long experience with urothelial toxicity resulting from exposure to the herbicide diuron. Currently, we are adopting in vitro approaches using human bladder cells (1T1) exposed to diuron and its metabolites to confirm the mitochondrial damage and to identify the intracellular pathways that are compromised after exposure. We suggest that the mitochondrial impairment in urothelial cells leads to urothelial injury/death followed by regenerative cell proliferation and hyperplasia, culminating in urothelial tumors.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1261||Mitochondrial impairment||Mitochondrial impairment|
|2||KE||1762||Urothelial cell injury/death||cell injury|
|3||KE||795||Increase, Regenerative cell proliferation (urothelial cells)||Increase, Regenerative cell proliferation (urothelial cells)|
|4||KE||796||Increase, Hyperplasia (urothelial)||Increase, Hyperplasia (urothelial)|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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Nascimento MG, de Oliveira ML, Lima AS, de Camargo JL. Effects of Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] on the urinary bladder of male Wistar rats. Toxicology. 5;224(1-2):66-73. 2006.