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Relationship: 2076

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

Decreased, 11KT leads to Impaired, Spermatogenesis

Upstream event

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

Decreased, 11KT

Downstream event

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

Impaired, Spermatogenesis

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
PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone	adjacent	High	Not Specified	Arthur Author (send email)	Open for citation & comment
Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory	adjacent	High	Moderate	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development

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
teleost fish	teleost fish	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	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

Androgens are critical for maintaining the normal male reproductive system (Tang, H., et al. 2018). Of these androgens, 11-KT has been identified as the most important in teleost fish (Borg, B. 1994). 11-KT is produced by the cyp11c1 encoded enzyme, 11ß-hydroxylase (Zheng, et al. 2020). 11-KT has been shown to bind to the androgen receptor with similar affinity as testosterone in zebrafish (Jorgensen, et al. 2007). It is well documented that 11-KT is involved in spermatogenesis, spermiation, male secondary sexual characteristics, and breeding behaviors (Geraudie, P. et al. 2010; Amer, M.A. et al. 2001). 11-KT is needed for the inducement of spermatogenesis and sperm production in teleost fish, with 10 ng/ml 11-KT being sufficient to induce full spermatogenesis in the Japanese eel (Miura, C. and T. Miura 2011). The mechanism through which 11-KT induces spermatogenesis is believed to be via activation of Sertoli cells and activin B (Miura et al. 2011; Miura et al. 2001; Sales, C.F., et al. 2020; Cavaco J.E.B., et al. 1998). 11-KT is not responsible for the acquisition of sperm motility in salmonids (Miura, et al. 1992).

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

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

In a study by Hatef, A. et al. (2012), treatment with the anti-androgen vinclozolin at 100 μg/L saw an increase in 11-KT levels with no significant change to spermatogenesis. This is consistent with other studies provided. Additionally, treatment at 400 μg/L saw no significant change in 11-KT levels with a decrease in spermatogenesis (although this decrease may not be statistically significant). The reason for these increases in 11-KT remains unknown; however, it is hypothesized that it is due to competitive androgen receptor binding.

Ozaki et al. (2006) showed that treatment with 100 ng/ml of cortisol significantly increased 11-KT levels. However, the less concentrated doses only saw non-significant increases in 11-KT with significant increases in spermatogenesis observed in all but the lowest dose. Despite this, Ozaki et al. make the generalization that cortisol treatment increased 11-KT and, in turn, spermatogenesis.

The study by Runnalls et al. (2007) saw treatment with Clofibric acid caused no significant changes to 11-KT levels, but that the levels did appear lower. Additionally, these treatments saw no significant effect on sperm number, but did see a significant increase in the number of non-viable sperm.

In a study by Zhang, Q., et al. (2020), cyp11c1 knockout did not completely block spermatogenesis. Zhang et al. explain this could be due to other androgens (11β-hydroxyandrostenedione and testosterone) compensating for the reduction in 11-KT, as they can both bind to the androgen receptor to influence downstream signaling.

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

Decreases in 11-KT levels were also seen with decreases in spermatogenesis in several studies (see table above).

10 ng/ml of 11-KT has been shown to be needed to induce full spermatogenesis in Japanese eel (Amer, M.A. et al. 2001; Miura, C. et al. 2011).

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

Taxonomic:

11-KT is the main androgen in teleost fish (Borg, B. 1994).

Sex Applicability:

11-KT is present in both male and female fish; however, spermatogenesis is a male-specific process.

Life Stage Applicability:

Spermatogenesis is observable in male fish that have reached the reproductive stage.