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Relationship: 3228

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, DHEA leads to Decrease, circulating testosterone levels

Upstream event

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

Reduction, DHEA

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 KER refers to part of steroidogenesis that includes the effects of decreased dehydroepiandrosterone (DHEA) levels that can lead to decreased testosterone levels. DHEA is converted to testosterone via one of the intermediates androstenedione or androstenediol by 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) and 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD). Therefore, effects on DHEA levels can have downstream effects on testosterone levels (Flück, 2017; Naamneh Elzenaty, 2022).

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

It is well established that DHEA is a precursor for testosterone (Flück, 2017; Naamneh Elzenaty, 2022).

Testosterone is produced in human Leydig cells from DHEA via androstenedione or androstenediol by the enzymes 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) and 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD). Testosterone is also synthesized from DHEA in human theca cells (Flück, 2017; Naamneh Elzenaty, 2022).

As DHEA is a precursor of testosterone, any effect on DHEA levels is expected to impact testosterone as well.

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

Exposure to stressors can lead to a decrease of DHEA that in turn leads to decrease of downstream hormones like testosterone.

Using H295R cells, exposure of ketoconazole resulted in a dose-dependent decreased in the levels of DHEA and testosterone (Nielsen et al., 2012). This was also observed using fluconazole on both H295R cells and its clonal cell line, HAC15 (van der Pas et al., 2012).

In female individuals with decreased libido, reduced levels of DHEA-sulfate, which represents a reservoir pool of DHEA, and testosterone have been observed (Guay et al., 2002). Oral supplementation with DHEA restores testosterone levels (Li etal., 2020; Liu et al., 2013).

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

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.

This KER is applicable to mammals, but DHEA from the Δ5 pathway is a precursor for testosterone mainly in humans, whereas in rodents the Δ4 pathway instead produces 17-OH-progesterone as the main precursor for testosterone (Flück, 2017; Naamneh Elzenaty, 2022).

Life stage applicability

DHEA is synthesized in the fetus and adult (Flück, 2017; Naamneh Elzenaty, 2022).

Sex applicability

Testosterone is synthesised from DHEA in both sexes, although at lower levels in 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.

Guay AT, Jacobson J. Decreased free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) levels in women with decreased libido. J Sex Marital Ther. 2002;28 Suppl 1:129-42. doi: 10.1080/00926230252851258. PMID: 11898695.

Li Y, Ren J, Li N, Liu J, Tan SC, Low TY, Ma Z. A dose-response and meta-analysis of dehydroepiandrosterone (DHEA) supplementation on testosterone levels: perinatal prediction of randomized clinical trials. Exp Gerontol. 2020 Nov;141:111110. doi: 10.1016/j.exger.2020.111110. Epub 2020 Oct 10. PMID: 33045358.

Liu TC, Lin CH, Huang CY, Ivy JL, Kuo CH. Effect of acute DHEA administration on free testosterone in middle-aged and young men following high-intensity interval training. Eur J Appl Physiol. 2013 Jul;113(7):1783-92. doi: 10.1007/s00421-013-2607-x. Epub 2013 Feb 17. PMID: 23417481.

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.

Nielsen, F. K., Hansen, C. H., Fey, J. A., Hansen, M., Jacobsen, N. W., Halling-Sørensen, B., Björklund, E., & Styrishave, B. (2012). H295R cells as a model for steroidogenic disruption: A broader perspective using simultaneous chemical analysis of 7 key steroid hormones. Toxicology in Vitro, 26(2), 343–350. https://doi.org/10.1016/j.tiv.2011.12.008

van der Pas, R., Hofland, L. J., Hofland, J., Taylor, A. E., Arlt, W., Steenbergen, J., van Koetsveld, P. M., de Herder, W. W., de Jong, F. H., & Feelders, R. A. (2012). Fluconazole inhibits human adrenocortical steroidogenesis in vitro. Journal of Endocrinology, 215(3), 403–412. https://doi.org/10.1530/JOE-12-0310