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Event: 1611

Key Event Title

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

Reduction, androstenedione

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

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
Cyp17A1 inhibition leads to undescended testes in mammals	KeyEvent	Bérénice COLLET (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
All life stages	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

Androstenedione is an intermediate in sex steroid biosynthesis being the precursor of steroid hormones like testosterone and estrone. Androstenedione is synthesised from 17-OH-progesterone by the enzyme CYP17A1 or from dehydroepiandrosterone (DHEA) by the enzyme 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD). Androstenedione can be converted to testosterone by the enzyme 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD3) and to estrone by the enzyme CYP19. A reduction in the upstream substrates or specific enzyme inhibition of CYP17A1 or 3-beta-HSD can result in reduced androstenedione levels (Burris-Hiday, 2021; Kepna, 2015; Naamneh Elzenaty, 2022; O'Donnell, 2022; Wróbel, 2023; Yadav, 2017; Ye, 2014).

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

There is no OECD test guideline for the measurement of androstenedione but androstenedione can be measured using a high-throughout assay using the H295R cell line (Karmaus, 2016). Competitive immunoenzymatic colorimetric methods (ELISA) for quantitative determination of androstenedione concentration in serum or plasma are available.

Androstenedione synthesis can be monitored using radiolabeled steroid precursor in association with High Performance Liquid Chromatography (HPLC). During synthesis, steroids will incorporate the radioactive label which can be afterwards, used for quantification. First of all, HPLC combined with internal standards can be used for steroids collection, fractionation and identification. Once separated from the other steroids, androstenedione can be finally quantified using liquid scintillation spectrometry.

Considerations for measurement of hormone levels have been described by ECHA and EFSA (2018) and Stanislaus (2012).

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

Androstenedione is present in mammals. There is a species difference in the synthesis of androstenedione. The precursor in rodents is mainly 17-OH-progesterone whereas the precursor in humans and primates is mainly DHEA since conversion of 17-OH-progesterone to androstenedione is inefficient (O'Donnell, 2022).

Life stage applicability

Androstenedione is present from fetal period throughout life (Naamneh Elzenaty, 2022).

Sex applicability

Androstenedione is present both in males and females (Naamneh Elzenaty, 2022).

References

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

Burris-Hiday SD, and Scott EE. 2021. ‘Steroidogenic Cytochrome P450 17A1 Structure and Function.’ Molecular and Cellular Endocrinology 528 (May): 111261. https://doi.org/10.1016/j.mce.2021.111261.

ECHA and EFSA (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, 135 pp. https://doi.org/10.2903/j.efsa.2018.5311. ECHA-18-G-01-EN.

Karmaus AL, Colleen M. Toole, Dayne L. Filer, Kenneth C. Lewis, Matthew T. Martin, High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells, Toxicological Sciences, Volume 150, Issue 2, April 2016, Pages 323–332, https://doi.org/10.1093/toxsci/kfw002

Kempná P, Marti N, Udhane S, and Flück CE. 2015. ‘Regulation of Androgen Biosynthesis - A Short Review and Preliminary Results from the Hyperandrogenic Starvation NCI-H295R Cell Model.’ Molecular and Cellular Endocrinology 408 (June): 124–32. https://doi.org/10.1016/j.mce.2014.12.015.

Naamneh Elzenaty R, du Toit T, and Flück CE. 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.

O’Donnell L, Whiley PAF, and Loveland KL. 2022. ‘Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis.’ Frontiers in Endocrinology 13: 898876. https://doi.org/10.3389/fendo.2022.898876.

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

Wróbel TM, Jørgensen FS, Pandey AV, Grudzińska A, Sharma K, Yakubu J, and Björkling F. 2023. ‘Non-Steroidal CYP17A1 Inhibitors: Discovery and Assessment.’ Journal of Medicinal Chemistry 66 (10): 6542–66. https://doi.org/10.1021/acs.jmedchem.3c00442.

Yadav R, Petrunak EM, Estrada DF, and Scott EE. 2017. ‘Structural Insights into the Function of Steroidogenic Cytochrome P450 17A1.’ Molecular and Cellular Endocrinology 441 (February): 68–75. https://doi.org/10.1016/j.mce.2016.08.035.

Ye L, Guo J, and Ge RS. 2014. ‘Environmental Pollutants and Hydroxysteroid Dehydrogenases.’ Vitamins and Hormones 94: 349–90. https://doi.org/10.1016/B978-0-12-800095-3.00013-4.