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Event: 1690

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Decrease, testosterone levels

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Decrease, testosterone levels
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
blood

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
hormone biosynthetic process testosterone decreased
testosterone decreased
testosterone biosynthetic process testosterone decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Decreased testosterone synthesis leading to short AGD KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development
Decreased COUP-TFII in Leydig cells leads to Impaired, Spermatogenesis KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite
HMGCR inhibition to male fertility KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome
PPARα activation leading to impaired fertility KeyEvent Arthur Author (send email) Open for citation & comment Under Review
PPAR and reproductive toxicity KeyEvent Evgeniia Kazymova (send email) Not under active development Under Development
Androgen receptor agonism leading to reproduction dysfunction KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite
Adult Leydig Cell Dysfunction KeyEvent Allie Always (send email) Under Development: Contributions and Comments Welcome
5α-reductase- Leydig tumor KeyEvent Arthur Author (send email) Under Development: Contributions and Comments Welcome
Cyp17A1 inhibition leads to undescended testes in mammals KeyEvent Evgeniia Kazymova (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Life Stages

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

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Testosterone is an endogenous steroid hormone and a potent androgen. Androgens act by binding androgen receptors in androgen-responsive tissues (Murashima et al., 2015). Testosterone and other androgens such as dihydrotestosterone (DHT) are important for reproductive development and masculinization of the fetus. Androgens are also important for bone, brain, muscle and skin health (Alemany, 2022). Just like other steroid hormones, testosterone is produced through a process known as steroidogenesis which is controlled by enzymes converting cholesterol into all of the downstream steroid hormones. In steroidogenesis, androstenedione or androstenediol is converted to testosterone by the enzymes 17β-hydroxysteroid dehydrogenase (HSD) or 3β-HSD, respectively. Testosterone can then be converted to the more potent androgen, DHT, by 5α-reductase, or aromatized by aromatase (CYP19A1) into estrogens. Testosterone secreted in blood circulation can be found free but more frequently is found bound to SHBG or albumin (Trost & Mulhall, 2016).

Testosterone is produced mainly by the ovaries (in females ), testes (in males), and to  a lesser degree in the adrenal glands. During fetal development testosterone plays a crucial role in the differentiation of male reproductive tissues and the overall male phenotype. In adulthood, testosterone synthesis is controlled by the Hypothalamus-Pituitary-Gonadal (HPG) axis. GnRH is released from the hypothalamus inducing LH pulses secreted by the anterior pituitary. This LH surge leads to increased testosterone production. If testosterone reaches low levels, this axis is once again stimulated to provoke more testosterone synthesis. This feedback loop is essential for maintenance of appropriate testosterone levels (Chandrashekar & Bartke, 1998; Ellis et al., 1983; Rey, 2021).

Disruption of any of the aforementioned processes may result in reduced testosterone levels, such as inhibition of steroidogenic enzyme activity thereby inhibiting production of testosterone.

General role in biology

Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation at puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behaviour. Apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain (Heemers, Verhoeven, & Swinnen, 2006). Androgens, principally T and 5α-dihydrotestosterone (DHT), exert most of their effects by interacting with a specific receptor, the androgen receptor (AR), for review see (Murashima, Kishigami, Thomson, & Yamada, 2015). On the one hand, testosterone can be reduced by 5α-reductase to produce 5α dihydrotestosterone (DHT). On the other hand, testosterone can be aromatized to generate estrogens. Testosterone effects can also be classified by the age of usual occurrence, postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Quantification of testosterone levels can be performed by various means (e.g. serum levels in vivo, cell culture medium levels in vitro, tissue ex vivo or in vitro). Traditional immunoassay methods (ELISA or RIA), and advanced instrumental techniques (e.g. LC-MS/MS) or liquid scintillation spectrometry (after radiolabeling) can be used (Shiraishi et al., 2008).

The H295R Steroidogenesis assay (OECD TG 456) is used to measure mainly the production of estradiol and testosterone. This is a validated OECD test guideline using adrenal H295R cells and hormone levels are then measured in the cell medium (OECD 2011). H295R adrenocortical carcinoma cells produce all the main enzymes and hormones of the steroidogenic pathway. Therefore, exposure to different stressors allows for broad analysis of their impact on steroidogenesis by measuring hormones in culture medium by LC-MS/MS. H295 assay was designed measure disruption to testosterone or estradiol levels but can now also be used to measure additional steroid hormones such as progesterone or pregnenolone. The U.S. EPA’s ToxCast program developed a high throughput method for the H295R assay which can measure a total of 11 hormones from the steroidogenesis pathway (Haggard et al., 2018). The H295R can be considered an indirect measurement as it provides information on a disruption of overall steroidogenesis that would result in a change of testosterone levels but not the underlying mechanism.

Testosterone can be measured by immunoassays and by isotope-dilution gas chromatography-mass spectrometry in serum (Taieb et al., 2003), (Paduch et al., 2014). Testosterone levels are measured i.a. in: Fish Lifecycle Toxicity Test (FLCTT) (US EPA OPPTS 850.1500), Male pubertal assay (PP Male Assay) (US EPA OPPTS 890.1500), OECD TG 441: Hershberger Bioassay in Rats (H Assay).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

This KE is applicable to mammals since the role of testosterone and its synthesis are conserved (Vitousek et al., 2018). Both sexes need, and produce, testosterone and its role is observed throughout different life stages, from development to adulthood (Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022). Therefore, this KE is also applicable to both males and females as well as throughout these life stages. Also of note, key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, it is acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability beyond mammals to other vertebrates.

Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.

References

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

Alemany, M. (2022). The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. International Journal of Molecular Sciences, 23(19), 11952. https://doi.org/10.3390/ijms231911952

Baker, M.E. (2011). Insights from the structure of estrogen receptor into the evolution of estrogens: implications for endocrine disruption. Biochem Pharmacol, 82(1), 1-8. https://doi.org/10.1016/j.bcp.2011.03.008

Chandrashekar, V., & Bartke, A. (1998). The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats*. Endocrinology, 139(3), 1067–1074. https://doi.org/10.1210/endo.139.3.5816

Ellis, G. B., Desjardins, C., & Fraser, H. M. (1983). Control of Pulsatile LH Release in Male Rats. Neuroendocrinology, 37(3), 177–183. https://doi.org/10.1159/000123540

Haggard, D. E., Karmaus, A. L., Martin, M. T., Judson, R. S., Setzer, R. W., & Paul Friedman, K. (2018). High-Throughput H295R Steroidogenesis Assay: Utility as an Alternative and a Statistical Approach to Characterize Effects on Steroidogenesis. Toxicological Sciences, 162(2), 509–534. https://doi.org/10.1093/toxsci/kfx274

Heemers, H. V, Verhoeven, G., & Swinnen, J. V. (2006). Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Molecular Endocrinology (Baltimore, Md.), 20(10), 2265–77. doi:10.1210/me.2005-0479

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

Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1849(2), 163–170. https://doi.org/10.1016/j.bbagrm.2014.05.020

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

Paduch, D. A., Brannigan, R. E., Fuchs, E. F., Kim, E. D., Marmar, J. L., & Sandlow, J. I. (2014). The laboratory diagnosis of testosterone deficiency. Urology, 83(5), 980–8. doi:10.1016/j.urology.2013.12.024

Rey, R. A. (2021). The Role of Androgen Signaling in Male Sexual Development at Puberty. Endocrinology, 162(2). https://doi.org/10.1210/endocr/bqaa215

Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., & Wang, C. (2008). Simultaneous Measurement of Serum Testosterone and Dihydrotestosterone by Liquid Chromatography–Tandem Mass Spectrometry. Clinical Chemistry, 54(11), 1855–1863. https://doi.org/10.1373/clinchem.2008.103846

Taieb, J., Mathian, B., Millot, F., Patricot, M.-C., Mathieu, E., Queyrel, N., … Boudou, P. (2003). Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clinical Chemistry, 49(8), 1381–95.

Trost, L. W., & Mulhall, J. P. (2016). Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials. The Journal of Sexual Medicine, 13(7), 1029–1046. https://doi.org/10.1016/j.jsxm.2016.04.068

Vitousek, M. N., Johnson, M. A., Donald, J. W., Francis, C. D., Fuxjager, M. J., Goymann, W., Hau, M., Husak, J. F., Kircher, B. K., Knapp, R., Martin, L. B., Miller, E. T., Schoenle, L. A., Uehling, J. J., & Williams, T. D. (2018). HormoneBase, a population-level database of steroid hormone levels across vertebrates. Scientific Data, 5(1), 180097. https://doi.org/10.1038/sdata.2018.97