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Relationship: 5

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

Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations

Upstream event

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

Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Downstream event

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

Reduction, Plasma 17beta-estradiol concentrations

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
Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female	adjacent	High		Allie Always (send email)	Open for citation & comment	EAGMST Under Review
Aromatase inhibition leading to reproductive dysfunction	adjacent	High	Moderate	Cataia Ives (send email)	Open for citation & comment	WPHA/WNT Endorsed
Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	adjacent	High	Low	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed
Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation	adjacent	High	Moderate	Allie Always (send email)	Under Development: Contributions and Comments Welcome
Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription	adjacent			Evgeniia Kazymova (send email)	Under Development: Contributions and Comments Welcome
Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR	adjacent	High	Moderate	Arthur Author (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
human	Homo sapiens		NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	High	NCBI
fathead minnow	Pimephales promelas	Moderate	NCBI
Fundulus heteroclitus	Fundulus heteroclitus	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

Term	Evidence
Adult, reproductively mature	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

See plausibility, below.

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance
The endocrine system: an overview	S Hiller-Sturmhöfel

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Based on the limited set of studies available to date, there are no known inconsistencies.

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

At present we are unaware of any well established quantitative relationships between ex vivo E2 production (as an indirect measure of granulosa cell E2 synthesis) and plasma E2 concentrations.

There are considerable data available which might support the development of such a relationship. Additionally, there are a number of existing mathematical/computational models of ovarian steroidogenesis (Breen et al. 2013; Shoemaker et al. 2010) and/or physiologically-based pharmacokinetic models of the hypothalamic-pituitary-gonadal axis (e.g., (Li et al. 2011a) that may be adaptable to support a quantitative understanding of this linkage.

• The Breen et al. 2013 model was developed based on in vivo time-course data for fathead minnow and incorporates prediction of compensatory responses resulting from feedback mechanisms operating as part of the hypothalamic-pituitary-gonadal axis.

• The Shoemaker et al. 2010 model is chimeric and includes signaling pathways and aspects of transcriptional regulation based on a mixture of fish-specific and mammalian sources.

• The Li et al. 2011 model is a PBPK-based model that was calibrated from data from fathead minnows, including controls and fish exposed to either 17alpha ethynylestradiol or 17beta trenbolone.

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

Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). While some E2 synthesis can occur in other tissues, the ovary is recognized as the major source of 17β-estradiol synthesis in female vertebrates. Endocrine actions of ovarian E2 are facilitated through transport via the plasma. Consequently, this key event relationship is applicable to most female vertebrates.