This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1384

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

Agonism, Androgen receptor leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Upstream event

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

Agonism, Androgen receptor

Downstream event

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

Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

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
Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	non-adjacent	Moderate	Low	Stephen Edwards (send email)	Open for citation & comment	WPHA/WNT Endorsed

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
fathead minnow	Pimephales promelas	Moderate	NCBI
Fundulus heteroclitus	Fundulus heteroclitus	Moderate	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	Moderate

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

At present, a direct structural/functional link between androgen receptor agonism and reduced estradiol synthesis by ovarian granulosa cells is not known. The linkage is thought to operate indirectly via endocrine feedback along the hypothalamic-pituitary-gonadal axis and subsequent effects on the regulation of enzymes involved in ovarian steroidogenesis. This relationship is primarily supported by association/correlation.

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

Updated 2017-03-17.

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

Synthesis of the steroidogenic enzymes that catalyze the formation of testosterone from cholesterol as a precursor as well as 17ß-estradiol (E2) from testosterone is stimulated by gonadotropins whose synthesis and secretion are in turn regulated by gonadotropin releasing hormone (GnRH) released from the hypothalamus (Payne and Hales 2004; Norris 2007; Miller 1988). Strong AR agonists are thought to exert negative feedback along the hypothalamic-pituitary-gonadal axis, leading to decreased stimulation of the steroidogenic pathway and subsequent declines in E2 production.

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

Direct support for the effect of AR agonists on estrogen production by ovary tissue:

Ekman et al. (2011) reported reductions in ex vivo E2 production by ovary tissue collected from fathead minnows exposed to 17ß-trenbolone in vivo. However, among four exposure durations assessed (1, 2, 4, 8 d), E2 production was only reduced following 2 d of exposure.
Glinka et al. (2015) reported reductions in E2 production in female Fundulus heteroclitus following 21 d of exposure to 0.5 or 5.0 ug 5alpha-dihydrotestosterone.
Rutherford et al. (2015) demonstrate reduced E2 production in Fundulus heteroclitus following exposure to 100 ug 5alpha-dihydrotestosterone (a non-aromatizable androgen) or 0.1 and 1.0 ug methyltestosterone (an aromatizable androgen) for 14 d,
Sharpe et al. (2004) reported reductions in E2 production in female Fundulus heteroclitus following exposure to 0.25 or 1.0 ug methyltestosterone/L for 7d, and in females exposed to 0.001, 0.01, or 0.1 ug methyltestosterone/L for 14 d.

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

The work of Ekman et al. (2011) demonstrates the effects can be transient due to complex compensatory behaviors.

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, the scope of data for associating AR-activation potency with decreased E2 production is not sufficient to describe a quantitative response-response relationship.

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

This KER is potentially applicable to sexually mature, female, vertebrates.

Androgen receptor orthologs are primarily limited to vertebrates (Baker 1997; Thornton 2001; Eick and Thornton 2011; Markov and Laudet 2011).
Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Markov et al. 2009; Baker 2011).

References

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

Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135(2): 101-107.
Baker ME. 2011. Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334: 14-20.
Eick GN, Thornton JW. 2011. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology 334(1-2): 31-38.
Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinović-Weigelt D, Kahl MD, Jensen KM, Durhan EJ, Makynen EA, Ankley GT, Collette TW. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17β-trenbolone in fish. Environ Toxicol Chem. 2011 Feb;30(2):319-29. doi: 10.1002/etc.406.
Markov GV, Laudet V. 2011. Origin and evolution of the ligand-binding ability of nuclear receptors. Molecular and cellular endocrinology 334(1-2): 21-30.
Markov GV, Tavares R, Dauphin-Villemant C, Demeneix BA, Baker ME, Laudet V. Independent elaboration of steroid hormone signaling pathways in metazoans. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11913-8. doi: 10.1073/pnas.0812138106.
Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25(6): 947-970.
Thornton JW. 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America 98(10): 5671-5676.