This AOP is licensed under a Creative Commons Attribution 4.0 International License.
PPARgamma activation leading to sarcomas in rats, mice, and hamsters
- Charles Wood
|Author status||OECD status||OECD project||SAAOP status|
|Under Development: Contributions and Comments Welcome||1.29||Under Development|
This AOP was last modified on February 07, 2020 14:46
|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|
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.