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Event: 2272

Key Event Title

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

Testosterone levels, increased

Short name

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Biological Context

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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

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
testosterone biosynthetic process	testosterone	increased

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

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 androgen steroid hormone. Androgens, such as testosterone, induce their effects through binding to the androgen receptor in androgen-responsive tissues (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Murashima et al., 2015; Naamneh Elzenaty et al., 2022).

The majority of testosterone in males is produced by the testes, while testosterone precursors are produced in theca cells in the ovaries of females and in the adrenal cortex of both sexes and converted into testosterone in peripheral tissues (Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022).

Testosterone is synthesized from cholesterol by the steroidogenic enzymes, with the main precursors of testosterone being androstenedione and androstenediol, which are converted by 17β-hydroxysteroid dehydrogenase (17β-HSD) or 3β-hydroxysteroid dehydrogenase (3β-HSD), respectively. Testosterone can also be converted into 17β-estradiol by the aromatase enzyme (CYP19) or into the more potent androgen, dihydrotestosterone (DHT), by 5α-reductase in various tissues (Ghosh, 2023; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022). Circulating testosterone is mainly found bound to albumin or sex hormone-binding globulin (Trost & Mulhall, 2016).

The hypothalamus-pituitary-gonadal (HPG) axis regulates testosterone synthesis in gonads of adults. At puberty, this axis is activated, leading to the release of gonadotropin releasing hormone (GnRH) from the hypothalamus, which induces a surge of luteinizing hormone (LH) from the anterior pituitary, subsequently increasing testosterone production in the gonads. The HPG axis is regulated by a feed-back loop to maintain appropriate testosterone levels (Jin & Yang, 2014; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022; Rey, 2021).

Normal testosterone levels are essential for sexual development and reproduction, as well as for the function of other organs and tissues such as adipose tissue, bone, brain, cardiovascular system, hair, muscle and skin (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022).

Perturbation of the HPG axis or the steroidogenesis pathway described above may lead to altered levels of testosterone, including increased testosterone levels.

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

Testosterone levels can be measured using immunoassays (enzyme linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), with sample preparation varying depending on the matrix of interest. Measurements can be made in serum, plasma, tissues or cell culture medium (Shiraishi et al., 2008; Trost & Mulhall, 2016). Considerations for measurement of hormone levels have been described (ECHA & EFSA, 2018; Chapin & Creasy, 2012; Hsing et al., 2007; Stanislaus et al., 2012).

The validated OECD test guideline TG456 is a steroidogenesis assay used to measure the levels of testosterone and 17β-estradiol. This assay utilizes H295R adrenocortical carcinoma cells that are capable of producing the principal hormones and enzymes of the steroidogenesis pathway. The cell culture media can be collected and analysed for hormone levels using LC-MS/MS. The aim of the assay is to identify substances that affect steroidogenesis resulting in increased or decreased levels of testosterone or 17β-estradiol (OECD, 2023). However, it should be recognized that any effect on testosterone levels in these cells is not necessary directly translatable to the in vivo scenario.

Domain of Applicability

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

Taxonomic applicability.

Testosterone is a main androgen in mammals, birds and amphibians, whereas 11-ketotestosterone is the main androgen in fish (Vitousek et al., 2018). The biologically plausible domain of taxonomic applicability is mammals, birds and amphibians since testosterone is present in these groups. The empirical domain of taxonomic applicability is human, rat and mice where testosterone 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

Testosterone is synthesized from the fetal period throughout adult life (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022).

Sex applicability

Testosterone is synthesized in both males and females (Naamneh Elzenaty et al., 2022).

References

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

ECHA and EFSA with the technical support of JRC, Andersson, N. et al., (2018). Guidance for the identiﬁcation of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA Journal 2018;16(6):5311. https://doi.org/10.2903/j.efsa.2018.5311

Chapin, R. E., & Creasy, D. M. (2012). Assessment of Circulating Hormones in Regulatory Toxicity Studies II. Male Reproductive Hormones. Toxicologic Pathology, 40(7), 1063–1078. https://doi.org/10.1177/0192623312443321

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

Ghosh, D. (2023). Structures and Functions of Human Placental Aromatase and Steroid Sulfatase, Two Key Enzymes in Estrogen Biosynthesis. Steroids 196 (August): 109249. https://doi.org/10.1016/j.steroids.2023.109249

Hsing, A. W., Stanczyk, F. Z., Bélanger, A., Schroeder, P., Chang, L., Falk, R. T., & Fears, T. R. (2007). Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry. Cancer Epidemiology Biomarkers and Prevention, 16(5), 1004–1008. https://doi.org/10.1158/1055-9965.EPI-06-0792

Jin J. M., & Yang W. X. (2014). Molecular regulation of hypothalamus-pituitary-gonads axis in males. Gene. Nov 1;551(1):15-25. https://doi.org/10.1016/j.gene.2014.08.048

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

OECD (2023). Test No. 456: H295R Steroidogenesis Assay, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264122642-en

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

Stanislaus, D., Andersson, H., Chapin, R., Creasy, D., Ferguson, D., Gilbert, M., Rosol, T. J., Boyce, R. W., & Wood, C. E. (2012). Society of Toxicologic Pathology Position Paper: Review Series: Assessment of Circulating Hormones in Nonclinical Toxicity Studies: General Concepts and Considerations. Toxicologic Pathology, 40(6), 943–950. https://doi.org/10.1177/0192623312444622

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