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Event: 274

Key Event Title

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

Reduction, Testosterone synthesis by ovarian theca cells

Short name

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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
Cellular

Cell 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

Cell term
theca cell

Organ term

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	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
Androgen receptor agonism leading to reproductive dysfunction	KeyEvent	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed

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
fathead minnow	Pimephales promelas	High	NCBI
Fundulus heteroclitus	Fundulus heteroclitus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult, reproductively mature	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Female	Not Specified

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 synthesized in ovarian theca cells through a series of enzyme catalyzed reactions that convert cholesterol to androgens (see KEGG reference pathway 00140 for details; www.genome.jp/kegg; (Payne and Hales 2004; Magoffin 2005; Young and McNeilly 2010). Binding of luteinizing hormone to luteinizing hormone receptors located on the surface of theca cell membranes leads to increased expression of steriodogenic cytochrome P450s, steroidogeneic acute regulatory protein, and consequent increases in androgen production (Payne and Hales 2004; Miller 1988; Miller and Strauss 1999).

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

Steroid production by isolated primary theca cells can be measured using radioimmunoassay or enzyme linked immunosorbent assay approaches (e.g., (Benninghoff and Thomas 2006; Campbell et al. 1998). However, the isolation and culture methods are not trivial. Similarly, development of immortalized theca cell lines has proven challenging (Havelock et al. 2004). Consequently, this key event is perhaps best evaluated by examining T production by intact ovarian tissue explants either exposed to chemicals in vitro (e.g., (Villeneuve et al. 2007; McMaster ME 1995) or in vivo (i.e., via ex vivo steroidogenesis assay; e.g., (Ankley et al. 2007)). Reductions in T production by ovarian tissue explants can indicate either direct inhibition of steriodogenic enzymes involved in T synthesis, or indirect impacts due to feedback along the hypothalamic-pituitary-gonadal axis (in cases where chemical exposures occur in vivo). However, because T synthesis in the theca cells is closely linked to estradiol (E2) synthesis by granulosa cells, reductions in T production by intact ovary tissue can also be due to increased aromatase activity and the resulting increased rate of converting T to E2.

Domain of Applicability

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

This key event is relevant to vertebrates and amphioxus, but not invertebrates.

Cytochrome P45011a (Cyp11a), a rate limiting enzyme for the production of testosterone, is specific to vertebrates and amphioxus (Markov et al. 2009; Baker et al. 2011; Payne and Hales, 2004).
Cyp11a does not occur in invertebrates, as a result, they do not synthesize testosterone, nor other steroid intermediates required for testosterone synthesis (Markov et al. 2009; Payne and Hales, 2004).

References

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

Ankley GT, Jensen KM, Kahl MD, Makynen EA, Blake LS, Greene KJ, et al. 2007. Ketoconazole in the fathead minnow (Pimephales promelas): reproductive toxicity and biological compensation. Environ Toxicol Chem 26(6): 1214-1223.
Baker ME. 2011. Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334: 14-20.
Benninghoff AD, Thomas P. 2006. Gonadotropin regulation of testosterone production by primary cultured theca and granulosa cells of Atlantic croaker: I. Novel role of CaMKs and interactions between calcium- and adenylyl cyclase-dependent pathways. General and comparative endocrinology 147(3): 276-287.
Campbell BK, Baird DT, Webb R. 1998. Effects of dose of LH on androgen production and luteinization of ovine theca cells cultured in a serum-free system. Journal of reproduction and fertility 112(1): 69-77.
Havelock JC, Rainey WE, Carr BR. 2004. Ovarian granulosa cell lines. Molecular and cellular endocrinology 228(1-2): 67-78.
Magoffin DA. 2005. Ovarian theca cell. The international journal of biochemistry & cell biology 37(7): 1344-1349.
Markov GV, Tavares R, Dauphin-Villemant C, Demeneix BA, Baker ME, Laudet V. Independent elaboration of steroid hormone signaling pathways in metazoans. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11913-8. doi: 10.1073/pnas.0812138106.
McMaster ME MK, Jardine JJ, Robinson RD, Van Der Kraak GJ. 1995. Protocol for measuring in vitro steroid production by fish gonadal tissue. Canadian Technical Report of Fisheries and Aquatic Sciences 1961 1961: 1-78.
Miller WL, Strauss JF, 3rd. 1999. Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. The Journal of steroid biochemistry and molecular biology 69(1-6): 131-141.
Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25(6): 947-970
Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, et al. 2007. Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol Environ Saf 68(1): 20-32.
Young JM, McNeilly AS. 2010. Theca: the forgotten cell of the ovarian follicle. Reproduction 140(4): 489-504.