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Relationship: 3836

Title

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, AhR leads to Progesterone resistance

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Activation, AhR

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Progesterone resistance

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
AhR activation leading to endometriosis	adjacent			Léna CAUDAL (send email)	Under development: Not open for comment. Do not cite

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
Homo sapiens	Homo sapiens	High	NCBI

Sex Applicability

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

Sex	Evidence
Female	High

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

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

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

(Igarashi et al. 2005) demonstrated that, in a co-culture model of human endometrial stromal and epithelial cells, exposure to increasing concentrations of TCDD (0.1 to 20 nM) resulted in a dose-dependent decrease in both PR-B mRNA and protein in stromal cells. This reduction led to a decreased PR-A/PR-B ratio, similar to that observed in patients with endometriosis, a condition characterized by progesterone resistance. Consistently, (Nayyar et al. 2007) reported that adult mice exposed in vivo to TCDD (10 µg/kg) at different developmental stages exhibited a progressive loss of both PR-A and PR-B isoforms in the uterus, with a more pronounced decrease as the number of exposures increased. Finally, (Resuehr et al. 2012) confirmed these findings in isolated human endometrial stromal cells cultured for 5 days in the presence of estradiol and progesterone, with or without TCDD (10 nM) : TCDD exposure resulted in a statistically significant decrease in PR-B mRNA expression. Collectively, these data indicate that activation of AhR by dioxin-like xenobiotics selectively represses PR-B, thereby altering the functional balance of progesterone signaling and potentially contributing to progesterone resistance in the endometrium.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

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

Time-scale

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

References

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

Igarashi, Toshio M., Kaylon L. Bruner-Tran, Grant R. Yeaman, et al. 2005b. ‘Reduced Expression of Progesterone Receptor-B in the Endometrium of Women with Endometriosis and in Cocultures of Endometrial Cells Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin’. Fertility and Sterility 84 (1): 67–74. https://doi.org/10.1016/j.fertnstert.2005.01.113.

Nayyar, Tultul, Kaylon L. Bruner-Tran, Dagmara Piestrzeniewicz-Ulanska, and Kevin G. Osteen. 2007. ‘Developmental Exposure of Mice to TCDD Elicits a Similar Uterine Phenotype in Adult Animals as Observed in Women with Endometriosis’. Reproductive Toxicology 23 (3): 326–36. https://doi.org/10.1016/j.reprotox.2006.09.007.

Resuehr, David, Dana R. Glore, Hugh S. Taylor, Kaylon L. Bruner-Tran, and Kevin G. Osteen. 2012. ‘Progesterone-Dependent Regulation of Endometrial Cannabinoid Receptor Type 1 (CB1-R) Expression Is Disrupted in Women with Endometriosis and in Isolated Stromal Cells Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)’. Fertility and Sterility 98 (4): 948-956.e1. https://doi.org/10.1016/j.fertnstert.2012.06.009.