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Relationship: 3518

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, 17βHSD3 activity leads to Decrease, circulating testosterone levels

Upstream event

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

Decreased, 17βHSD3 activity

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

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	Moderate

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

17-beta-HSD3 is a hydroxysteroid (17-beta) dehydrogenase with its 17-ketosteroid reductase activity that catalyses the conversion of androstenedione into testosterone with NADPH as a cofactor. It is expressed mainly in the testes and to a lesser extent in the brain and adipose tissue (Corbould et al., 2002; Mindnich et al., 2004; Payne & Hales, 2004).

An inhibition of 17-beta-HSD3 would lead to less conversion of androstenedione to testosterone and therefore a decrease in testosterone levels.

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

Conversion from the less potent androgen, androstenedione, to testosterone is known to be performed by the enzymatic activity of 17-beta-HSD3. This reaction is essential for testosterone synthesis in testis (Mindnich et al., 2004; Payne & Hales, 2004). This is reflected in deficiencies of 17-beta-HSD3, which is the most common deficiency when it comes to issues with androgen synthesis. This deficiency usually results in disorder of sexual development (DSD). Patients with mutations in this enzyme have higher levels of circulating androstenedione, lower levels of testosterone, and present with ambiguous poorly masculinized genitalia (Bertelloni et al., 2009; Lawrence et al., 2022).

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

Several chemicals have been designed to inhibit the activity of 17-beta-HSD3, usually to be used to treat prostate cancer as the enzyme is overexpressed leading to increased T levels and increased proliferation of prostate cancer cells (Marchais-Oberwinkler et al., 2011).

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

A knockout mouse study has raised concerns regarding the difference between species. It shows that even when 17-beta-HSD3 is knocked out, male mice can maintain intratesticular levels of testosterone and are fertile with correct spermatogenesis. This shows that there may be another enzyme responsible for synthesis of testosterone in mice when 17-beta-HSD3 is not present (Lawrence et al., 2022).

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

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

Although testosterone and 17-beta-HSD3 is important for other vertebrates, this KER focuses on mammals (Mindnich et al., 2004).

Life stage applicability

Finally, it has been shown that the role of 17-beta-HSD3 in catalysing the synthesis of testosterone occurs throughout all life stages (Mindnich et al., 2004).

Sex applicability

This KER is applicable to males and females as 17-beta-HSD3 is expressed in both. However, it seems more essential to male testicular testosterone synthesis as shown by the effect of 17-beta-HSD3 deficiencies observed mainly in men (Bertelloni et al., 2009; Corbould et al., 2002).

References

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

Bertelloni, S., Dati, E., & Hiort, O. (2009). Diagnosis of 17β-hydroxysteroid dehydrogenase deficiency. Expert Review of Endocrinology & Metabolism, 4(1), 53–65. https://doi.org/10.1586/17446651.4.1.53

Corbould, A., Bawden, M., Lavranos, T., Rodgers, R., & Judd, S. (2002). The effect of obesity on the ratio of type 3 17β-hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra-abdominal adipose tissue of women. International Journal of Obesity, 26(2), 165–175. https://doi.org/10.1038/sj.ijo.0801886

Lawrence, B. M., O’Donnell, L., Smith, L. B., & Rebourcet, D. (2022). New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice. International Journal of Molecular Sciences, 23(24), 15555. https://doi.org/10.3390/ijms232415555

Marchais-Oberwinkler, S., Henn, C., Möller, G., Klein, T., Negri, M., Oster, A., Spadaro, A., Werth, R., Wetzel, M., Xu, K., Frotscher, M., Hartmann, R. W., & Adamski, J. (2011). 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development. The Journal of Steroid Biochemistry and Molecular Biology, 125(1–2), 66–82. https://doi.org/10.1016/j.jsbmb.2010.12.013

Mindnich, R., Möller, G., & Adamski, J. (2004). The role of 17 beta-hydroxysteroid dehydrogenases. Molecular and Cellular Endocrinology, 218(1–2), 7–20. https://doi.org/10.1016/j.mce.2003.12.006

Payne, A. H., & Hales, D. B. (2004). Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones. Endocrine Reviews, 25(6), 947–970. https://doi.org/10.1210/er.2003-0030