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Relationship: 256


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

demethylation, PPARg promoter leads to Decrease, Aromatase (Cyp19a1)

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

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

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

This KER establishes the link between PPAR activation and levels of aromatase. Aromatase is a key enzyme in steroidogenesis, catalysing the conversion of androgens to estrogens.

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
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

Peroxisome proliferator-activated receptors (PPARs) are master switches of lipid metabolism and cell differentiation, their role was also acknowledge in regulation of reproductive function and development [reviewed by (Froment et al., 2006)]. In particular PPARγ was found to be critically involved in follicular development, ovulation, maintenance of corpus luteum during pregnancy, and maturation and function of placenta (Barak et al., 1999). The PPARs are implicated in regulation of steroidogenesis in vitro [reviewed by (Carolyn M Komar, 2005)]. The PPARγ is activated upon the ligand binding in granulosa cells, and then indirectly alters the expression of aromatase, rate-limiting enzyme in conversion of androgens to estrogenes (Richards, 1980) and other enzymes involved in steroidogenesis (Dupont, Chabrolle, Ramé, Tosca, & Coyral-Castel, 2008). Moreover there is evidence of implication of another isoform of PPAR in the effect on aromatase, the PPARα (Lovekamp-Swan, Jetten, & Davis, 2003).

In the ovary all PPAR isoforms have been detected in both human and rodent ovary (Braissant, Foufelle, Scotto, Dauça, & Wahli, 1996), (C M Komar, Braissant, Wahli, & Curry, 2001), (Lambe & Tugwood, 1996) reviewed (Carolyn M Komar, 2005). In female rats the PPAR was detected in estradiol producing cells and is involved in the regulation of fertility:

• PPARγ is primarily expressed in the granulosa cells and preovulatory follicles, less strongly expressed in the theca cells and in corpus luteum where it increases after ovulation (its expression falls after the LH surge ) (C M Komar et al., 2001). However, in the absence of fertilization or embryo implantation, PPARγ expression decreases as a result of corpus luteum regression (Viergutz, Loehrke, Poehland, Becker, & Kanitz, 2000). • PPARγ directly involved in oocyte maturation and ovulation [reviewed by (Froment et al., 2006)]. • PPAR α is found primarily in the theca and stroma, the expression of PPARα in granulosa cells is very low [reviewed by (Carolyn M Komar, 2005)] The precise molecular mechanism by which PPAR regulates aromatase is unclear given the fact that the proximal promoter regulating aromatase expression in the rat ovary does not contain an obvious peroxisome proliferator response element (PPRE) (Young & McPhaul, 1997). There are plausible ways in which the PPARγ could modify the transcript of aromatase, as transcriptionally active PPAR:RXR heterodimer, this includes: competition for binding sites on DNA and competition for limiting co-activators required for gene transcription. Previous studies show that both PPARγ and RXR ligands alone suppress aromatase activity in human granulosa cells, and combined treatment causes a greater reduction than either compound alone (Mu et al., 2000). The ovarian aromatase promoter contains one half of a PPRE, which is the binding site for steroidogenic factor 1 (SF-1) (Young & McPhaul, 1997). While it is unknown whether PPAR can compete for binding on an incomplete response element, disruption of SF-1 binding to this half site would disrupt normal aromatase transcription. Studies by (S. Plummer, Sharpe, Hallmark, Mahood, & Elcombe, 2007), (S. M. Plummer et al., 2013) showed that PPARα and SF1 share a common coactivator, CREB-binding protein (CBP), which is present in limiting concentrations (McCampbell, 2000). Binding of CBP to PPARα could therefore starve SF1 of a cofactor essential for its transactivation functions. Another possibility is that PPAR is able to modify protein–protein interactions involved in the transcription of aromatase. Activation of PPAR may recruit cofactors away from aromatase to inhibit normal transcription. Further study is necessary to determine how PPAR regulates aromatase transcription.

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

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

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


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