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Event: 413

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Reduction, Testosterone synthesis in Leydig cells

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. The short name should be less than 80 characters in length. More help
Reduction, Testosterone synthesis in Leydig cells

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Cell term
testosterone secreting cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action
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
PPAR and reproductive toxicity KeyEvent Elise Grignard (send email) Not under active development Under Development
PPARα activation leading to impaired fertility KeyEvent Elise Grignard (send email) Open for citation & comment EAGMST Under Review
Adult Leydig Cell Dysfunction KeyEvent Susan Laws (send email) Under Development: Contributions and Comments Welcome
Decreased testosterone synthesis leading to short AGD KeyEvent Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
mice Mus sp. Low NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

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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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Biological state

Testosterone is a steroid hormone from the androgen group and is found in humans and other vertebrates.

Biological compartments

In humans and other mammals, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females and other steroidogenic tissues (e.g., brain, adipose). It either acts locally /or is transported to other tissues via blood circulation. Testosterone synthesis takes place within the mitochondria of Leydig cells, the testosterone-producing cells of the testis. It is produced upon stimulation of these cells by Luteinizing hormone (LH) that is secreted in pulses into the peripheral circulation by the pituitary gland in response to Gonadotropin-releasing hormone (GnRH) from the hypothalamus. Testosterone and its aromatized product, estradiol, feed back to the hypothalamus and pituitary gland to suppress transiently LH and thus testosterone production. In response to reduced testosterone levels, GnRH and LH are produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone (Ellis, Desjardins, and Fraser 1983), (Chandrashekar and Bartke 1998).

General role in biology

Testosterone is the principal male sex hormone and an anabolic steroid. Male sexual differentiation depends on testosterone (T), dihydrotestosterone (DHT), and the expression of androgen receptors by target cells (Manson and Carr 2003). During the development secretion of androgens by Leydig cells is essential for masculinization of the foetus (Nef 2000). The foetal Leydig cells develop in utero. These cells become competent to produce testosterone in rat by gestational day (GD) 15.5, with increasing production thereafter. Peak steroidogenic activity is reached just prior to birth, on GD19 (Chen, Ge, and Zirkin 2009). Testosterone secreted by foetal Leydig cells is required for the differentiation of the male urogenital system late in gestation (Huhtaniemi and Pelliniemi 1992). Foetal Leydig cells also play a role in the scrotal descent of the testis through their synthesis of insulin-like growth factor 3 (Insl3), for review see (Nef 2000).

In humans, the first morphological sign of testicular differentiation is the formation of testicular cords, which can be seen between 6 and 7 weeks of gestation. Steroid-secreting Leydig cells can be seen in the testis at 8 weeks of gestation. At this period, the concentration of androgens in the testicular tissue and blood starts to rise, peaking at 14-16 weeks of gestation. This increase comes with an increase in the number of Leydig cells for review see (Rouiller-Fabre et al. 2009).

Adult Leydig cells, which are distinct from the foetal Leydig cells, form during puberty and supply the testosterone required for the onset of spermatogenesis, among other functions. Distinct stages of adult Leydig cell development have been identified and characterized. The stem Leydig cells are undifferentiated cells that are capable of indefinite self-renewal but also of differentiation to steroidogenic cells. These cells give rise to progenitor Leydig cells, which proliferate, continue to differentiate, and give rise to the immature Leydig cells. Immature Leydig cells synthesize high levels of testosterone metabolites and develop into terminally differentiated adult Leydig cells, which produce high levels of testosterone. With aging, both serum and testicular testosterone concentrations progressively decline, for review see (Nef 2000).

Androgens play a crucial role in the development and maintenance of male reproductive and sexual functions. Low levels of circulating androgens can cause disturbances in male sexual development, resulting in congenital abnormalities of the male reproductive tract. Later in life, this may cause reduced fertility, sexual dysfunction, decreased muscle formation and bone mineralisation, disturbances of fat metabolism, and cognitive dysfunction. Testosterone levels decrease as a process of ageing: signs and symptoms caused by this decline can be considered a normal part of ageing.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

OECD TG 456 [1] is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T). The testosterone syntheis can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM): Leydig Cell-enriched Cultures [2], Testicular Organ and Tissue Culture Systems [3].

Testosterone synthesis in vitro cultured cells can be measured indirectly by testosterone radioimmunoassay or analytical methods such as LC-MS.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.

Ellis, G B, C Desjardins, and H M Fraser. 1983. “Control of Pulsatile LH Release in Male Rats.” Neuroendocrinology 37 (3) (September): 177–83. Huhtaniemi, I, and L J Pelliniemi. 1992. “Fetal Leydig Cells: Cellular Origin, Morphology, Life Span, and Special Functional Features.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 201 (2) (November): 125–40.

Manson, Jeanne M, and Michael C Carr. 2003. “Molecular Epidemiology of Hypospadias: Review of Genetic and Environmental Risk Factors.” Birth Defects Research. Part A, Clinical and Molecular Teratology 67 (10) (October): 825–36. doi:10.1002/bdra.10084.

Nef, S. 2000. “Hormones in Male Sexual Development.” Genes & Development 14 (24) (December 15): 3075–3086. doi:10.1101/gad.843800.

Rouiller-Fabre, Virginie, Vincent Muczynski, Romain Lambrot, Charlotte Lécureuil, Hervé Coffigny, Catherine Pairault, Delphine Moison, et al. 2009. “Ontogenesis of Testicular Function in Humans.” Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 47 (5) (January): S19–24. doi:10.2478/v10042-009-0065-4.