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Relationship: 3229

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, androstenedione leads to Decrease, circulating testosterone levels

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Reduction, androstenedione
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Decrease, circulating testosterone levels

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
Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals) adjacent High High Bérénice COLLET (send email) Open for citation & comment

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
mammals mammals High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

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

This key event relationship links a decrease in androstenedione to a decrease in testosterone. 

17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) is an enzyme responsible for synthesis of testosterone from androstenedione, hence if androstenedione decrease, there will be a lack of substrate for this enzymatic reaction to occur, which may affect testosterone levels. Decreased levels of the precursor androstenedione results in reduced levels of testosterone (Flück, 2017; Lawrence, 2022; Naamneh Elzenaty, 2022; O’Donnell, 2022; Ye, 2014).

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

The KER describes a generally recognized and understood process, i.e. canonical knowledge. The aim of the literature search was therefore to identify review articles and book chapters that summarise the canonical knowledge. PubMed was searched using key words related to steroidogenesis. The search was restricted to reviews from the last 10 years.

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

The synthesis of testosterone from androstenedione by 17-beta-HSD is a well-studied and generally recognized process and the biological plausibility of the KER therefore is high. 

17-beta-HSD is an enzyme responsible for synthesis of testosterone from androstenedione. There are several isoforms of the enzyme. 17-beta-HSD3 is the main enzyme in humans converting androstenedione to testosterone, whereas both 17-beta-HSD1 and 17-beta-HSD3 can perform the conversion in rodents. Reduced levels of the precursor androstenedione will result in reduced levels of testosterone (Flück, 2017; Lawrence, 2022; Naamneh Elzenaty, 2022; O’Donnell, 2022; Ye, 2014).

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

Testosterone can also be synthesised by 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) from androstenediol. Reduced levels could therefore also be due to reduced levels of the precursor androstenediol.

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
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

Taxonomic applicability

Androstenedione and testosterone are present in mammals (O'Donnell, 2022). 

Life stage applicability 

Androstenedione and testosterone are present from fetal period throughout life (Naamneh Elzenaty, 2022). 

Sex applicability 

Androstenedione and testosterone are present both in males and females (Naamneh Elzenaty, 2022).

References

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

Flück CE & Pandey AV (2017). Testicular Steroidogenesis. In Simoni, M & Huhtaniemi IT (Eds.) Endocrinology of the Testis and Male Reproduction. (1st ed., pp. 343-371) Endocrinology. Cham: Springer International Publishing. https://doi.org/10.1007/978-3-319-44441-3. 

Karmaus AL, Colleen M. Toole, Dayne L. Filer, Kenneth C. Lewis, Matthew T. Martin, High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells, Toxicological Sciences, Volume 150, Issue 2, April 2016, Pages 323–332, https://doi.org/10.1093/toxsci/kfw002 

Lawrence BM, O’Donnell L, Smith LB, and Rebourcet D. 2022. ‘New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice.’ International Journal of Molecular Sciences 23 (24). https://doi.org/10.3390/ijms232415555. 

Naamneh Elzenaty R, du Toit T, and Flück CE. 2022. ‘Basics of Androgen Synthesis and Action.’ Best Practice & Research. Clinical Endocrinology & Metabolism 36 (4): 101665. https://doi.org/10.1016/j.beem.2022.101665. 

O’Donnell L, Whiley PAF, and Loveland KL. 2022. ‘Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis.’ Frontiers in Endocrinology 13: 898876. https://doi.org/10.3389/fendo.2022.898876. 

Ye L, Guo J, and Ge RS. 2014. ‘Environmental Pollutants and Hydroxysteroid Dehydrogenases.’ Vitamins and Hormones 94: 349–90. https://doi.org/10.1016/B978-0-12-800095-3.00013-4.