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Relationship: 1229


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, PPARα leads to Increase, Phenotypic enzyme activity

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
PPARα activation leading to hepatocellular adenomas and carcinomas in rodents adjacent High High Chris Corton (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Activation of the PPARα receptor leads to a coordinated gene expression program that produces lipid metabolizing enzymes and proteins associated with control of the cell cycle.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Neither peroxisome proliferation nor increased enzyme activity is observed in PPARα-null mice. (Belury et al. 1998; Peters et al. 1997)

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Similar to other nuclear receptors such as the aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR), PPARα induces a coordinated gene expression program (Corton et al. 2014; Elcombe et al. 2014; Budinsky et al. 2014).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Vanishingly few, if any.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating factors include NF-kB activation, cytokines, oxidative stress, and the role of microRNAs.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

The enzyme response does not occur until at least 14 MIE units and then rises with a slope of 0.72 per MIE unit.

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The time scale of both the MIE and the enzyme response is 1 week.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Increased expression of ACO and associated oxidative stress activated NF-kB

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The domain of applicability is similar to that for the overall MIE.


List of the literature that was cited for this KER description. More help

Anderson, S. P., Dunn, C., Laughter, A., Yoon, L., Swanson, C., Stulnig, T. M., Steffensen, K. R., Chandraratna, R. A., Gustafsson, J. A., & Corton, J. C. (2004). Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor alpha, retinoid X receptor, and liver X receptor in mouse liver. Mol Pharmacol, 66(6), 1440-1452.

Belury, M. A., Moya-Camarena, S. Y., Sun, H., Snyder, E., Davis, J. W., Cunningham, M. L., & Vanden Heuvel, J. P. (1998). Comparison of dose-response relationships for induction of lipid metabolizing and growth regulatory genes by peroxisome proliferators in rat liver. Toxicol Appl Pharmacol, 151(2), 254-261.

Budinsky, R. A., Schrenk, D., Simon, T., Van den Berg, M., Reichard, J. F., Silkworth, J. B., Aylward, L. L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T. B., Walker, N. J., & Rowlands, J. C. (2014). Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study. Crit Rev Toxicol, 44(1), 83-119.

Corton, J. C., Apte, U., Anderson, S. P., Limaye, P., Yoon, L., Latendresse, J., Dunn, C., Everitt, J. I., Voss, K. A., Swanson, C., Kimbrough, C., Wong, J. S., Gill, S. S., Chandraratna, R. A., Kwak, M. K., Kensler, T. W., Stulnig, T. M., Steffensen, K. R., Gustafsson, J. A., . . . Mehendale, H. M. (2004). Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem, 279(44), 46204-46212.

Corton, J. C., Cunningham, M. L., Hummer, T. B., Lau, C, Meek, B, Peters, JM, Popp, JA, Rhomberg, L, Seed, J., & Klaunig, J. E. (2014). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol, 44(1), 1-49.

Elcombe, C. R., Elcombe, B. M., Foster, J. R., Chang, S. C., Ehresman, D. J., & Butenhoff, J. L. (2012). Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARα and CAR/PXR. Toxicology, 293(1-3), 16-29.

Cunningham, M. L., Collins, B. J., Hejtmancik, M. R., Herbert, R. A., Travlos, G. S., Vallant, M. K., & Stout, M. D. (2010). Effects of the PPARα Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism. PPAR Res, 2010.

Fitzgerald, J. E., Sanyer, J. L., Schardein, J. L., Lake, R. S., McGuire, E. J., & de la Iglesia, F. A. (1981). Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil. J Natl Cancer Inst, 67(5), 1105-1116.

Hartig, F., Stegmeier, K., Hebold, G., Özel, M., & Fahimi, H. D. (1982). Study of liver enzymes: peroxisome proliferation and tumor rates in rats at the end of carcinogenicity studies with bezafibrate and clofibrate. Annals of the New York Academy of Sciences, 386(1), 464-467.

Lutz, W. K., & Lutz, R. W. (2009). Statistical model to estimate a threshold dose and its confidence limits for the analysis of sublinear dose-response relationships, exemplified for mutagenicity data. Mutat Res, 678(2), 118-122.

NTP (2007). Toxicity studies of WY-14,643 (CAS No. 50892-23-4) administered in feed to male Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters. Toxic Rep Ser, 62), 1-136.

Peters, J. M., Cattley, R. C., & Gonzalez, F. J. (1997). Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis, 18(11), 2029-2033.