Aop: 37

AOP Title


PPARalpha-dependent liver cancer

Short name:


PPARalpha-dependent liver cancer

Graphical Representation


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J. Christopher Corton, 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 (corton.chris@epa.gov)

Point of Contact


Chris Corton   (email point of contact)



  • Chris Corton



Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.17 Included in OECD Work Plan

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


Revision dates for related pages

Page Revision Date/Time
Activation, PPARα September 16, 2017 10:14
modulation, Genes/proteins that regulate hepatocyte fate December 03, 2016 16:37
Increase, Mitogenic cell proliferation (hepatocytes) December 20, 2018 15:21
Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci December 03, 2016 16:37
Increase, Adenomas/carcinomas (hepatocellular) September 16, 2017 10:16
modulation, Genes/proteins that regulate hepatocyte fate leads to Increase, Mitogenic cell proliferation (hepatocytes) December 03, 2016 16:38
Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci leads to Increase, Adenomas/carcinomas (hepatocellular) December 03, 2016 16:38
Increase, Mitogenic cell proliferation (hepatocytes) leads to Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci December 03, 2016 16:38
Activation, PPARα leads to modulation, Genes/proteins that regulate hepatocyte fate December 03, 2016 16:38
pirinixic acid November 29, 2016 18:42
Clofibrate November 29, 2016 18:42
Bis(2-ethylhexyl) phthalate November 29, 2016 18:42
Nafenopin November 29, 2016 18:42
ciprofibrate November 29, 2016 18:42
Gemfibrozil March 31, 2020 10:24
PERFLUOROOCTANOIC ACID November 29, 2016 18:42
Bezafibrate November 29, 2016 18:42
Fenofibrate November 29, 2016 18:42



Several therapeutic agents and industrial chemicals induce liver tumors in rats and mice through the activation of the peroxisome proliferator-activated receptor alpha (PPARa). The molecular and cellular events by which PPARa activators induce rodent hepatocarcinogenesis have been extensively studied and elucidated. The weight of evidence relevant to the hypothesized AOP for PPARa activator-induced rodent hepatocarcinogenesis is summarized here. Chemical-specific and mechanistic data support concordance of temporal and dose–response relationships for the key events associated with many PPARa activators including a phthalate ester plasticizer di(2-ethylhexyl)phthalate (DEHP) and the drug gemfibrozil. The key events (KE) identified are KE1–PPARa activation, KE2–alteration in cell growth pathways, KE3–perturbation of cell growth and survival including increases in cell proliferation and effects on apoptosis, KE4–selective clonal expansion of preneoplastic foci cells, which lead to the Adverse Outcome–increases in hepatocellular adenomas and carcinomas. A number of molecular events were identified which were initially evaluated as possible key events. However, the data were not convincing for these to be key events in the MOA. Rather, although not causal these modulating factors were considered to have the potential to alter the ability of PPARa activators to increase liver cancer. These modulating events include increases in oxidative stress, activation of NF-kB, and inhibition of gap junction intercellular communication. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARa activators, are unlikely to induce liver tumors in humans because of biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels.

Background (optional)


Summary of the AOP


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 227 Activation, PPARα Activation, PPARα
2 KE 1170 modulation, Genes/proteins that regulate hepatocyte fate modulation, Genes/proteins that regulate hepatocyte fate
3 KE 716 Increase, Mitogenic cell proliferation (hepatocytes) Increase, Mitogenic cell proliferation (hepatocytes)
4 KE 1171 Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci
5 AO 719 Increase, Adenomas/carcinomas (hepatocellular) Increase, Adenomas/carcinomas (hepatocellular)

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
modulation, Genes/proteins that regulate hepatocyte fate leads to Increase, Mitogenic cell proliferation (hepatocytes) adjacent High Moderate
Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci leads to Increase, Adenomas/carcinomas (hepatocellular) adjacent High Moderate
Increase, Mitogenic cell proliferation (hepatocytes) leads to Increase, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci adjacent High Moderate
Activation, PPARα leads to modulation, Genes/proteins that regulate hepatocyte fate non-adjacent High Moderate

Network View





Life Stage Applicability


Life stage Evidence
Adult High

Taxonomic Applicability


Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability


Sex Evidence
Male High
Female High

Overall Assessment of the AOP


Consider the following criteria (may include references to KE Relationship pages): 1. concordance of dose-response relationships; 2. temporal concordance among the key events and adverse effect; 3. strength, consistency, and specificity of association of adverse effect and initiating event; 4. biological plausibility, coherence, and consistency of the experimental evidence; 5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP; 6. uncertainties, inconsistencies and data gaps.

Domain of Applicability


Essentiality of the Key Events


Evidence Assessment


Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)


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