Aop:37

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AOP Title

PPARalpha-dependent liver cancer
Short name: PPARalpha-dependent liver cancer

Authors

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)

Status

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Alert: The Weight of Evidence column in the Molecular Initiating Event and Key Event tables has changed to Essentiality. Consider re-evaluating the columns in these tables. Alert: Molecular Initiating Event not specified on page. Alert: Adverse Outcome not specified on page.

OECD Project 1.17: CAR and PPARα-mediated pathways to non-genotoxic rodent liver cancer.

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

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Abstract

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.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
PPARα, Activation Strong

Key Events

Event Support for Essentiality
Genes/proteins that regulate hepatocyte fate, modulation Strong
Mitogenic cell proliferation (hepatocytes), Increase Strong
Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci, Increase Strong
Oxidative Stress, Increase Moderate
Nuclear factor kappa B (NF-kB), Increase activation Weak
Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids, Increase Moderate
NADPH Oxidase, Activation Weak
Genes involved in fatty acid oxidation, Increase Weak

Adverse Outcome

Adverse Outcome
Adenomas/carcinomas (hepatocellular), Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Genes/proteins that regulate hepatocyte fate, modulation Directly Leads to Mitogenic cell proliferation (hepatocytes), Increase Strong Moderate
Genes/proteins that regulate hepatocyte fate, modulation Directly Leads to Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci, Increase Moderate Moderate
Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci, Increase Directly Leads to Adenomas/carcinomas (hepatocellular), Increase Strong Moderate
PPARα, Activation Directly Leads to Genes involved in fatty acid oxidation, Increase Strong Moderate
NADPH Oxidase, Activation Directly Leads to Oxidative Stress, Increase Moderate Weak
PPARα, Activation Indirectly Leads to NADPH Oxidase, Activation Weak Weak
Oxidative Stress, Increase Indirectly Leads to Nuclear factor kappa B (NF-kB), Increase activation Moderate Weak
Nuclear factor kappa B (NF-kB), Increase activation Indirectly Leads to Genes/proteins that regulate hepatocyte fate, modulation Weak Weak
Mitogenic cell proliferation (hepatocytes), Increase Directly Leads to Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci, Increase Strong Moderate
Genes involved in fatty acid oxidation, Increase Directly Leads to Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids, Increase Strong Strong
Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids, Increase Directly Leads to Oxidative Stress, Increase Strong Moderate
PPARα, Activation Indirectly Leads to Genes/proteins that regulate hepatocyte fate, modulation Strong Moderate

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Life Stage Applicability

Life Stage Evidence Links
Adult Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Strong NCBI
Syrian hamster Mesocricetus auratus Weak NCBI
guinea pig Cavia porcellus Weak NCBI
Monkey sp. unidentified monkey Weak NCBI
human Homo sapiens Weak NCBI

Sex Applicability

Sex Evidence Links
Male Strong
Female Strong

Graphical Representation

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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.

Weight of Evidence Summary

Summary Table
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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.

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

Applicability of the AOP

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.

Considerations for Potential Applications of the AOP (optional)

References

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