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a,bNathalia P Souza, a,bThania RR Lima, b,cLilian C Pereira, a,bJoao Lauro V de Camargo
aBotucatu Medical School, UNESP – Sao Paulo State University, Botucatu Campus, Department of Pathology. bCenter for Evaluation of Environmental Impact on Human Health (TOXICAM), Botucatu, SP, Brazil. cSchool of Agricultural Sciences, UNESP - Sao Paulo State University, Botucatu Campus, Department of Bioprocesses and Biotechnology, Botucatu, SP, Brazil.
Point of Contact
Nathalia Pereira Souza (email point of contact)
- 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 Do not cite|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
Events: Molecular Initiating Events (MIE)
|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)
Fava RM, Ferragut Cardoso AP, da Rocha MS, Nascimento E Pontes MG, de Camargo JL, de Oliveira ML. Evaluation of early changes induced by diuron in the rat urinary bladder using different processing methods for scanning electron microscopy. Toxicology. 3;333:100-6. 2015.
Ihlaseh-Catalano SM, Bailey KA, Cardoso AP, Ren H, Fry RC, de Camargo JL, Wolf DC. Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron. Toxicology. 5;325:21-30. 2014
Da Rocha MS, Arnold LL, De Oliveira ML, Catalano SM, Cardoso AP, Pontes MG, Ferrucio B, Dodmane PR, Cohen SM, De Camargo JL. Diuron-induced rat urinary bladder carcinogenesis: mode of action and human relevance evaluations using the International Programme on Chemical Safety framework. Crit Rev Toxicol. 44(5):393-406. 2014.
Da Rocha MS, Arnold LL, Dodmane PR, Pennington KL, Qiu F, De Camargo JL, Cohen SM. Diuron metabolites and urothelial cytotoxicity: in vivo, in vitro and molecular approaches. Toxicology. 15;314(2-3):238-46. 2013.
Cardoso AP, Ihlaseh Catalano SM, da Rocha MS, Nascimento E Pontes MG, de Camargo JL, de Oliveira ML. Dose-response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats. Toxicology. 4;312:1-5. 2013.
Da Rocha MS, Arnold LL, Pennington KL, Muirhead D, Dodmane PR, Anwar MM, Battalora M, De Camargo JL, Cohen SM. Diuron-induced rat bladder epithelial cytotoxicity. Toxicol Sci. 130(2):281-8. 2012.
Ihlaseh SM, Bailey KA, Hester SD, Jones C, Ren H, Cardoso AP, Oliveira ML, Wolf DC, de Camargo JL. Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action. Toxicol Sci.122(2):330-8. 2011.
da Rocha MS, Nascimento MG, Cardoso AP, de Lima PL, Zelandi EA, de Camargo JL, de Oliveira ML. Cytotoxicity and regenerative proliferation as the mode of action for diuron-induced urothelial carcinogenesis in the rat. Toxicol Sci. 113(1):37-44. 2010.
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.