Aop:163

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/163


AOP Title

PPARgamma activation leading to sarcomas in rats, mice, and hamsters
Short name: PPARgamma-related sarcomas

Authors

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)

Status

Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

This AOP page was last modified on 12/11/2016.

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Abstract

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)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
PPAR-gamma activation, Activation of specific nuclear receptors Strong

Key Events

Event Support for Essentiality
adipogenesis, Increased Strong
secretion of local growth factors, Increased Strong
proliferation of mesenchymal cells, Increased Strong
IGF-1 (mouse), Increased Moderate
Firbrosarcoma, Increased Moderate
liposarcoma, Increased Moderate
hemagiosarcoma, Increased Moderate

Adverse Outcome

Adverse Outcome

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
PPAR-gamma activation, Activation of specific nuclear receptors Indirectly Leads to adipogenesis, Increased Strong
PPAR-gamma activation, Activation of specific nuclear receptors Indirectly Leads to secretion of local growth factors, Increased Moderate
adipogenesis, Increased Directly Leads to secretion of local growth factors, Increased Strong
secretion of local growth factors, Increased Directly Leads to proliferation of mesenchymal cells, Increased Strong
secretion of local growth factors, Increased Directly Leads to IGF-1 (mouse), Increased Strong
proliferation of mesenchymal cells, Increased Directly Leads to Firbrosarcoma, Increased Strong
proliferation of mesenchymal cells, Increased Directly Leads to liposarcoma, Increased Strong
proliferation of mesenchymal cells, Increased Directly Leads to hemagiosarcoma, Increased Strong

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus rattus Rattus rattus Strong NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References

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.