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Relationship: 143

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, Gonadotropins, circulating concentrations leads to Reduction, Testosterone synthesis by ovarian theca cells

Upstream event

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

Reduction, Gonadotropins, circulating concentrations

Downstream event

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

Reduction, Testosterone synthesis by ovarian theca 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)	adjacent	High	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

In mammals androgen production by theca cells is largely under control of LH (Norris 2007; Young and McNeilly 2010).
In fish, the differential role of LH versus FSH has been more difficult to define, in part due to the inability to specifically measure LH and FSH in most fish species and the parallel fluctuations of LH and FSH expression in many species.
Regardless of the differential effects of the two gonadotropins there is little dispute that gonadotropins stimulate gonadal steroid production and that the production of androgens (e.g., androstenedione, testosterone), which are the precursors for estrogen synthesis occurs in the theca cells (Payne and Hales 2004; Young and McNeilly 2010; Miller 1988; Nagahama et al. 1993).

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 strong weight of evidence establishing the role of gonadotropins in stimulating gonadal steroidogenesis. This relationship is widely accepted.

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

No significant inconsistencies identified to date, although comprehensive literature review as not conducted.

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

Predictive quantitative relationships between circulating gonadotropin concentrations in fish and testosterone synthesis by ovarian theca cells have not been established.

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

A functional hypothalamic-pituitary-gonadal axis involving GnRH and gonadotropin-mediated regulation of reproductive functions is a vertebrate trait (Sower et al. 2009).
The taxonomic applicability of this key event is limited to chordates.
CYP11a, one of the critical enzymes for testosterone synthesis has only been found in amphioxus or vertebrates (Baker 2011). Consequently, taxonomic relevance of this KER is likely restricted to that domain.

References

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

Baker ME. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol. 2011 Mar 1;334(1-2):14-20. doi:10.1016/j.mce.2010.07.013.
Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
Nagahama Y, Yoshikumi M, Yamashita M, Sakai N, Tanaka M. 1993. Molecular endocrinology of oocyte growth and maturation in fish. Fish Physiology and Biochemistry 11: 3-14.
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.
Young JM, McNeilly AS. 2010. Theca: the forgotten cell of the ovarian follicle. Reproduction 140(4): 489-504.