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Event: 1611
Key Event Title
Reduction, androstenedione
Short name
Biological Context
Level of Biological Organization |
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Tissue |
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
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
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mammals | mammals | High | NCBI |
Life Stages
Life stage | Evidence |
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All life stages | High |
Sex Applicability
Term | Evidence |
---|---|
Mixed | High |
Key Event Description
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
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
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
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.