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Aop: 163

AOP Title

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PPARgamma activation leading to sarcomas in rats, mice, and hamsters

Short name:

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PPARgamma-related sarcomas

Graphical Representation

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Click to download graphical representation template

Authors

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Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

Point of Contact

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Charles Wood   (email point of contact)

Contributors

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  • Charles Wood

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite 1.29 Under Development


This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
Activation of specific nuclear receptors, PPAR-gamma activation September 16, 2017 10:17
Increased, adipogenesis September 16, 2017 10:17
Increased, secretion of local growth factors September 16, 2017 10:17
Increased, proliferation of mesenchymal cells September 16, 2017 10:17
Increased, IGF-1 (mouse) September 16, 2017 10:17
Increased, Firbrosarcoma September 16, 2017 10:17
Increased, liposarcoma September 16, 2017 10:17
Increased, hemagiosarcoma September 16, 2017 10:17
Activation of specific nuclear receptors, PPAR-gamma activation leads to Increased, adipogenesis December 03, 2016 16:38
Activation of specific nuclear receptors, PPAR-gamma activation leads to Increased, secretion of local growth factors December 03, 2016 16:38
Increased, adipogenesis leads to Increased, secretion of local growth factors December 03, 2016 16:38
Increased, secretion of local growth factors leads to Increased, proliferation of mesenchymal cells December 03, 2016 16:38
Increased, secretion of local growth factors leads to Increased, IGF-1 (mouse) December 03, 2016 16:38
Increased, proliferation of mesenchymal cells leads to Increased, Firbrosarcoma December 03, 2016 16:38
Increased, proliferation of mesenchymal cells leads to Increased, liposarcoma December 03, 2016 16:38
Increased, proliferation of mesenchymal cells leads to Increased, hemagiosarcoma December 03, 2016 16:38
Troglitazone November 29, 2016 18:42

Abstract

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This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.



Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1028 Activation of specific nuclear receptors, PPAR-gamma activation Activation of specific nuclear receptors, PPAR-gamma activation
2 KE 1029 Increased, adipogenesis Increased, adipogenesis
3 KE 1032 Increased, secretion of local growth factors Increased, secretion of local growth factors
4 KE 1033 Increased, proliferation of mesenchymal cells Increased, proliferation of mesenchymal cells
5 KE 1034 Increased, IGF-1 (mouse) Increased, IGF-1 (mouse)
6 KE 1035 Increased, Firbrosarcoma Increased, Firbrosarcoma
7 KE 1036 Increased, liposarcoma Increased, liposarcoma
8 KE 1037 Increased, hemagiosarcoma Increased, hemagiosarcoma

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Increased, adipogenesis leads to Increased, secretion of local growth factors adjacent High
Increased, secretion of local growth factors leads to Increased, proliferation of mesenchymal cells adjacent High
Increased, secretion of local growth factors leads to Increased, IGF-1 (mouse) adjacent High
Increased, proliferation of mesenchymal cells leads to Increased, Firbrosarcoma adjacent High
Increased, proliferation of mesenchymal cells leads to Increased, liposarcoma adjacent High
Increased, proliferation of mesenchymal cells leads to Increased, hemagiosarcoma adjacent High
Activation of specific nuclear receptors, PPAR-gamma activation leads to Increased, adipogenesis non-adjacent High
Activation of specific nuclear receptors, PPAR-gamma activation leads to Increased, secretion of local growth factors non-adjacent Moderate

Network View

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Stressors

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Name Evidence Term
Troglitazone

Life Stage Applicability

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Rattus rattus Rattus rattus High NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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1. Cohen, S. M. (2005). Effects of PPARgamma and combined agonists on the urinary tract of rats and other species. Toxicological sciences : an official journal of the Society of Toxicology 87(2), 322-7, 10.1093/toxsci/kfi266.

2. Hardisty, J. F., Elwell, M. R., Ernst, H., Greaves, P., Kolenda-Roberts, H., Malarkey, D. E., Mann, P. C., and Tellier, P. A. (2007). Histopathology of hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats associated with PPAR agonists. Toxicologic pathology 35(7), 928-41, 10.1080/01926230701748156.

3. Kakiuchi-Kiyota, S., Arnold, L. L., Yokohira, M., Koza-Taylor, P., Suzuki, S., Varney, M., Pennington, K. L., and Cohen, S. M. (2011a). Evaluation of direct and indirect effects of the PPARgamma agonist troglitazone on mouse endothelial cell proliferation. Toxicologic pathology 39(7), 1032-45, 10.1177/0192623311422080.

4. Kakiuchi-Kiyota, S., Arnold, L. L., Yokohira, M., Suzuki, S., Pennington, K. L., and Cohen, S. M. (2011b). Evaluation of PPARgamma agonists on rodent endothelial cell proliferation. Toxicology 287(1-3), 91-8, 10.1016/j.tox.2011.05.019.

5. Long, G. G., Reynolds, V. L., Dochterman, L. W., and Ryan, T. E. (2009). Neoplastic and non-neoplastic changes in F-344 rats treated with Naveglitazar, a gamma-dominant PPAR alpha/gamma agonist. Toxicologic pathology 37(6), 741-53, 10.1177/0192623309343775.