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Relationship: 31

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, Gonadotropins, circulating concentrations

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, Gonadotropins, circulating 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
Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	adjacent	Low	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	Low	NCBI

Sex Applicability

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

Sex	Evidence
Female	Not Specified

Life Stage Applicability

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

Term	Evidence
Adult, reproductively mature	Not Specified

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 biological 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 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

Circulating concentrations of steroid hormones are tightly regulated via positive and negative feedback loops that operate through endocrine, autocrine, and/or paracrine mechanisms within the hypothalamic-pituitary-gonadal axis (Norris 2007).
Gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion from the pituitary is a key regulator of gonadal steroid biosynthesis.
Negative feedback of androgens or estrogens at the level of the hypothalamus and/or pituitary can reduce gonadotropin secretion by pituitary gonadotropes either indirectly due to decreased GnRH signaling from the hypothalamus or directly through intrapituitary regulators of gonadotropin expression (e.g., activin, follistatin, inhibin) (Norris 2007; Habibi and Huggard 1998).
While similar processes of negative feedback of sex steroids on gonadotropin expression and release have been established in fish (Levavi-Sivan et al. 2010), there are many remaining uncertainties about the exact mechanisms through which feedback takes place in fish as well as other vertebrates. For example, feedback is thought to involve a complex interplay of neurotransmitter signaling, kisspeptins, and the follistatin/inhibin/activin system (Trudeau et al. 2000; Trudeau 1997; Oakley et al. 2009; Cheng et al. 2007).
In addition, the nature of the feedback produced by androgens is dependent on the concentration, form of the androgen (e.g., aromatizable versus non-aromatizable), life-stage and likely species (Habibi and Huggard 1998; Trudeau et al. 2000; Gopurappilly et al. 2013).
The specific mechanisms through which negative feedback of AR agonists on the hypothalamus and pituitary are mediated in fish are not fully understood.
- It is thought that GABAergic and dopaminergic neurons may be important mediators of sex steroid feedback on gonadotropin releasing hormone (GnRH) release from the hypothalamus (Trudeau et al. 2000; Trudeau 1997).
- More recent evidence also suggests an important role of kisspeptin neurons, which have been shown to express both AR and ERα are important mediators of feedback response to circulating androgen concentrations (Oakley et al. 2009).
- Follistatin expression in the pituitary has also been cited as a key regulator of gonadotropin expression that is directly regulated by androgens and estrogens (Cheng et al. 2007).
Regardless of the exact mechanisms, negative feedback of androgens on GnRH and/or gonadotropin release from the hypothalamus and/or pituitary is a well established endocrine phenomenon.

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

There is a relatively strong body of evidence demonstrating that gonadectomy and/or treatment with potent AR antagonists can increase circulating concentrations of gonadotropins in fish and that those effects can be reversed by treatment with testosterone (reviewed in (Habibi and Huggard 1998; Levavi-Sivan et al. 2010)).
However, we are currently unaware of any studies conducted with xenobiotic or pharmaceutical androgen agonists that measured effects on circulating gonadotropins.
Empirical support for this linkage is largely lacking for most fish species, as antibodies capable of specifically detecting and distinguishing luteinizing hormone and follicle stimulating hormone have not yet been developed, despite many attempts.
FSH and LH can be specifically measured for salmonids, but measurement methods for most other species are lacking.

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

Due to uncertainties regarding the exact mechanisms through which exogenous androgens mediate a negative feedback response this initiation of a negative feedback response is not directly observable. Negative feedback would generally be inferred through a decrease in gonadotropin release and associated declines in circulating gonadotropin concentrations.

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

Given the uncertainties in the specific mechanism(s) of negative feedback that are involved and the lack of data on circulating gonadotropin concentrations following exposure to exogenous androgen agonists there is currently no quantitative understanding that would translate relative binding affinity and/or effect concentrations in an AR-mediated transcriptional activation assay into expected impacts on circulating gonadotropin concentrations.

Quantitative understanding of this linkage is largely absent for fish due to lack of established methods for measuring the gonaodotropins and uncertainties about the exact mechanisms through which androgens or androgen receptor activation may exert negative feedback control on gonadotropin secretion.

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

At present, this relationship is assumed to operate in repeat spawning fish species with asynchronous oocyte development.

The extent to which the negative feedback mechanism proposed here is operable for fish species employing other reproductive strategies and/or for other vertebrates has not been extensively examined, to date.

References

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

Cheng GF, Yuen CW, Ge W. 2007. Evidence for the existence of a local activin follistatin negative feedback loop in the goldfish pituitary and its regulation by activin and gonadal steroids. The Journal of endocrinology 195(3): 373-384.
Gopurappilly R, Ogawa S, Parhar IS. 2013. Functional significance of GnRH and kisspeptin, and their cognate receptors in teleost reproduction. Frontiers in endocrinology 4: 24.
Habibi HR, Huggard DL. 1998. Testosterone regulation of gonadotropin production in goldfish. Comparative biochemistry and physiology Part C, Pharmacology, toxicology & endocrinology 119(3): 339-344.
Levavi-Sivan B, Bogerd J, Mananos EL, Gomez A, Lareyre JJ. 2010. Perspectives on fish gonadotropins and their receptors. General and comparative endocrinology 165(3): 412-437.
Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
Oakley AE, Clifton DK, Steiner RA. 2009. Kisspeptin signaling in the brain. Endocrine reviews 30(6): 713-743.
Trudeau VL, Spanswick D, Fraser EJ, Lariviére K, Crump D, Chiu S, et al. 2000. The role of amino acid neurotransmitters in the regulation of pituitary gonadotropin release in fish. Biochemistry and Cell Biology 78: 241-259.
Trudeau VL. 1997. Neuroendocrine regulation of gonadotropin II release and gonadal growth in the goldfish, Carassius auratus. Reviews of Reproduction 2: 55-68.