API

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Relationship: 3381

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

Dihydrotestosterone (DHT) levels, increased leads to Androgen receptor activation, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Dihydrotestosterone (DHT) levels, increased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Androgen receptor activation, increased

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 High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During development and at adulthood 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

Dihydrotestosterone (DHT) is an endogenous steroid hormone and a potent androgen. The biological effects of DHT are mediated by the androgen receptor (AR). Increased levels of DHT lead to increased AR activity in vivo, which results in effects on sexual development, as well as effects on other organs and tissues (Dalton et al., 2010; Luetjens et al., 2012; Naamneh Elzenaty et al., 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. A literature search was therefore performed to identify review articles and book chapter that summarise the canonical knowledge.

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 activation of AR by DHT is a generally recognized and understood process, i.e. canonical knowledge and the biological plausibility of the KER is considered high.

DHT, a potent endogenous androgen, exerts its effects through the AR. DHT is primarily synthesized from testosterone by the enzyme 5α-reductase, with different isoforms expressed in specific tissues and developmental stages. An alternative (“backdoor”) pathway exists for DHT formation that does not depend on testosterone as precursor. The AR belongs to the family of steroid hormone nuclear receptors. It contains three major domains essential for its activity: the N-terminal region, the ligand binding domain (LBD), and the DNA binding domain (DBD). The AR is in the cytoplasm in the absence of ligand. Upon binding of DHT, the receptor is activated, forms a homodimer, translocates into the nucleus and binds to androgen-response elements and regulates target gene transcription by recruiting cofactor protein complexes. The AR can also have rapid non-genomic actions by binding to plasma membrane proteins and activating kinase signalling in the cytoplasm. Increased levels of DHT results in increased AR activity in vivo that can affect numerous biological processes, including sexual development (e.g. differentiation of external genitalia and prostate), as well as effects on other organs and tissues such hair and skin (Azzouni et al., 2012; Dalton et al., 2010; Luetjens et al., 2012; Miller & Auchus, 2019; Naamneh Elzenaty et al., 2022; Sutinen et al., 2017; Swerdloff et al., 2017).

Prostate cancer in men is dependent on androgens and activation of the AR promotes growth of prostate cancer cells (Naamneh Elzenaty et al., 2022). Androgen deprivation is used as treatment including 5α-reductase inhibitors to reduce DHT levels (Aggarwal et al 2010).

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 uncertainties or inconsistences have been identified for the KER that is based on canonical knowledge.

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

No specific evidence for response-response relationships has been identified for the KER.

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

Effects on activation of the AR on cellular function can be seen after minutes to hours (Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

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

No specific evidence for feedforward or feedback loops has been identified for the KER.  

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

The AR that mediates the effect of DHT is present in vertebrates. Mammals, birds and amphibians have one AR gene, whereas some fish species have two genes (Ogino et al., 2018). DHT is present in mammals, fish, birds and amphibians (Dalton et al., 2010; Luetjens et al., 2012; Martin, 2020; Naamneh Elzenaty et al., 2022). The biologically plausible domain of taxonomic applicability is mammals, fish, birds and amphibians since DHT is present in these groups. The empirical domain of taxonomic applicability is human, rat and mice where DHT levels have been studied. The KE description focuses on mammals, but AOP developers are encouraged to expand the applicability to other species.

Life stage applicability

DHT is synthesized from fetal throughout adult life (Dalton et al., 2010; Luetjens et al., 2012; Naamneh Elzenaty et al., 2022).

Sex applicability

DHT is synthesized in both males and females (Naamneh Elzenaty et al., 2022). The evidence call is high due to the extensive knowledge on the role of DHT in males and females.

References

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

Aggarwal, S., Thareja S., Verma A., Bhardwaj T.R., and Kumar M (2010). An Overview on 5α-Reductase Inhibitors.  Steroids 75 (2): 109–53. https://doi.org/10.1016/j.steroids.2009.10.005

Azzouni, F., Godoy, A., Li, Y., & Mohler, J. (2012). The 5 alpha-reductase isozyme family: A review of basic biology and their role in human diseases. Adv Urol. 2012;2012:530121. https://doi.org/10.1155/2012/530121

Dalton, J. T., & Gao, W. (2010). Androgen Receptor. In Nuclear Receptors (pp. 143–182). Springer Netherlands. https://doi.org/10.1007/978-90-481-3303-1_6

Luetjens, C. M., & Weinbauer, G. F. (2012). Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions. In Testosterone (pp. 15–32). Cambridge University Press. https://doi.org/10.1017/CBO9781139003353.003

Martin, O., Ermler, S., McPhie, J., Scholze, M., Baynes, A. (2020). Data collection in support of the Endocrine Disruption (ED) assessment for non-target vertebrates. EFSA supporting publication 2020:EN-1849. 131 pp. https://doi.org/10.2903/sp.efsa.2020.EN-1849

Miller, W. L., & Auchus, R. J. (2019). The “backdoor pathway” of androgen synthesis in human male sexual development. PLoS Biol. 2019 Apr 3;17(4):e3000198. https://doi.org/10.1371/journal.pbio.3000198

Naamneh Elzenaty, R., du Toit, T., & Flück, C. E. (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

Ogino, Y., Tohyama, S., Kohno, S., Toyota, K., Yamada, G., Yatsu, R., Kobayashi, T., Tatarazako, N., Sato, T., Matsubara, H., Lange, A., Tyler, C.R., Katsu, Y., Iguchi, T., & Miyagawa, S. (2018). Functional distinctions associated with the diversity of sex steroid hormone receptors ESR and AR. The Journal of Steroid Biochemistry and Molecular Biology, 184, 38–46. https://doi.org/10.1016/j.jsbmb.2018.06.002

Sutinen, P., Malinen, M., & Palvimo, J. J. (2017). Androgen Receptor. In M. Simoni & I. T. Huhtaniemi (Eds.), Endocrinology of the Testis and Male Reproduction (pp. 395–416). Springer International Publishing. https://doi.org/10.1007/978-3-319-44441-3_12

Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., & Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, physiology, and clinical implications of elevated blood levels. Endocr Rev. 2017 Jun 1;38(3):220-254. https://doi.org/10.1210/er.2016-1067

U.S. EPA. (2024). ToxCast & Tox21 AR agonism of testosterone. Retrieved from Https://Www.Epa.Gov/Chemical-Research/Toxicity-Forecaster-Toxcasttm-Data June 23, 2023. Data Released October 2018.