API

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

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

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 Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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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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Stressors

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Name Evidence Term
Troglitazone

Molecular Initiating Event

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Title Short name
Activation of specific nuclear receptors, PPAR-gamma activation Activation of specific nuclear receptors, PPAR-gamma activation

Key Events

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Title Short name
Increased, adipogenesis Increased, adipogenesis
Increased, secretion of local growth factors Increased, secretion of local growth factors
Increased, proliferation of mesenchymal cells Increased, proliferation of mesenchymal cells
Increased, IGF-1 (mouse) Increased, IGF-1 (mouse)
Increased, Firbrosarcoma Increased, Firbrosarcoma
Increased, liposarcoma Increased, liposarcoma
Increased, hemagiosarcoma Increased, hemagiosarcoma

Adverse Outcome

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Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Taxonomic Applicability

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

Sex Applicability

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Graphical Representation

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Click to download graphical representation template

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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Weight of Evidence Summary

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Quantitative Considerations

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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.