Aopwiki

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Created at: 2019-01-04 09:03

AOP ID and Title:

AOP 163: PPARgamma activation leading to sarcomas in rats, mice, and hamsters
Short Title: 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

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 Do not cite 1.29 Under Development

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.




Summary of the AOP

Events

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

Key Event Relationships

Upstream Event Relationship Type Downstream Event Evidence Quantitative Understanding
Increased, adipogenesis adjacent Increased, secretion of local growth factors High
Increased, secretion of local growth factors adjacent Increased, proliferation of mesenchymal cells High
Increased, secretion of local growth factors adjacent Increased, IGF-1 (mouse) High
Increased, proliferation of mesenchymal cells adjacent Increased, Firbrosarcoma High
Increased, proliferation of mesenchymal cells adjacent Increased, liposarcoma High
Increased, proliferation of mesenchymal cells adjacent Increased, hemagiosarcoma High
Activation of specific nuclear receptors, PPAR-gamma activation non-adjacent Increased, adipogenesis High
Activation of specific nuclear receptors, PPAR-gamma activation non-adjacent Increased, secretion of local growth factors Moderate

Stressors


Name Evidence
Troglitazone

Overall Assessment of the AOP

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Rattus rattus Rattus rattus High NCBI
mouse Mus musculus Moderate NCBI

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.



Appendix 1

List of MIEs in this AOP

Event: 1028: Activation of specific nuclear receptors, PPAR-gamma activation

Short Name: Activation of specific nuclear receptors, PPAR-gamma activation

Key Event Component

Process Object Action
peroxisome proliferator activated receptor signaling pathway peroxisome proliferator-activated receptor gamma decreased

Stressors

Name
Tetrabromobisphenol A

Biological Context

Level of Biological Organization
Molecular

Cell term

Cell term
hepatocyte

Evidence for Perturbation by Stressor



Tetrabromobisphenol A

TBBPA binds to PPARγ in vitro, with a Kd of 0.78 µM and in vivo in zebrafish, with a LOEL of 100 nM  (Fang et al., 2015; Riu et al., 2011; Riu et al., 2014). Mild activation has also been reported in vitro in several research papers and in ToxCast assays as well, with effective doses ranging from 0.3 to 10 µM (Riu et al., 2011; Riu et al., 2014; Suzuki et al., 2013; ToxCastTM Data; Watt and Schlezinger, 2015).


List of Key Events in the AOP

Event: 1029: Increased, adipogenesis

Short Name: Increased, adipogenesis

Key Event Component

Process Object Action
fat cell differentiation increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
eukaryotic cell

Event: 1032: Increased, secretion of local growth factors

Short Name: Increased, secretion of local growth factors

Key Event Component

Process Object Action
secretion eukaryotic protein increased

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
eukaryotic cell

Event: 1033: Increased, proliferation of mesenchymal cells

Short Name: Increased, proliferation of mesenchymal cells

Key Event Component

Process Object Action
mesenchymal cell proliferation mesenchymal cell increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
mesenchymal cell

Event: 1034: Increased, IGF-1 (mouse)

Short Name: Increased, IGF-1 (mouse)

Key Event Component

Process Object Action
gene expression IGF-like family receptor 1 (mouse) increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
eukaryotic cell

Event: 1035: Increased, Firbrosarcoma

Short Name: Increased, Firbrosarcoma

Key Event Component

Process Object Action
Fibrosarcoma increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Tissue

Organ term

Organ term
fibrous connective tissue

Event: 1036: Increased, liposarcoma

Short Name: Increased, liposarcoma

Key Event Component

Process Object Action
liposarcoma increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Tissue

Organ term

Organ term
adipose tissue

Event: 1037: Increased, hemagiosarcoma

Short Name: Increased, hemagiosarcoma

Key Event Component

Process Object Action
hemangiosarcoma increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:163 - PPARgamma activation leading to sarcomas in rats, mice, and hamsters KeyEvent

Biological Context

Level of Biological Organization
Tissue

Organ term

Organ term
blood vessel endothelium

Appendix 2

List of Key Event Relationships in the AOP