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Event: 2320

Key Event Title

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

Decreased, 17-beta-HSD3 activity

Short name

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Decreased, 17βHSD3 activity

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Biological Context

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Level of Biological Organization
Molecular

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

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

Key Event Overview

AOPs Including This Key Event

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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	Moderate

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

The enzyme, 17-beta-HSD3, is part of the hydroxysteroid (17-beta) dehydrogenase family which play a key role in steroidogenesis. Mainly, the enzyme is implicated in the synthesis of sex steroids and is not involved in the synthesis of adrenal hormones (Payne & Hales, 2004; Sipilä et al., 2020). 17-beta-HSD3 mainly converts the weaker androgen, androstenedione, into the more potent androgen, testosterone (Payne & Hales, 2004; Shima et al., 2013), but it also catalyses the conversion of DHEA into androstenediol (Miller & Auchus, 2019). Additionally, it is important for the backdoor pathway, which produces DHT without testosterone as an intermediate. 17-beta-HSD3 can convert

androsterone to androstanediol, which will then be converted into DHT (Miller & Auchus, 2019). Its expression is mainly gonadotropin independent postnatally but once puberty begins, its expression depends on gonadotropins and androgens (Lawrence et al., 2022; Payne & Hales, 2004; Scott et al., 2009). It is also expressed in the adipose tissue of both males and females (Corbould et al., 2002; Mindnich et al., 2004).

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

No OECD standardized test guideline is available for the measurement of 17-beta-HSD3 activity.

Several studies measure this activity by using cells expressing 17-beta-HSD3. A substrate is added to the media and the enzyme activity is measured as the conversion to testosterone. This was done using different cell lines (HEK293, MDA-MB453, LNCaP, and 293-EBNA cells) (Day et al., 2009; Spires et al., 2005).

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.

This KE focuses on mammals although 17-beta-HSD3 is expressed in vertebrates as a whole (Mindnich et al., 2004).

Life stage applicability

17-beta-HSD3 is expressed during fetal development in Sertoli cells. Postnatally and during adulthood it is expressed in Leydig cells (Mindnich et al., 2004). The KE is applicable to all life stages.

Sex applicability

17-beta-HSD3 is expressed in testis as it is essential for testosterone synthesis. It is also expressed in the adipose tissue of both males and females (Corbould et al., 2002; Mindnich et al., 2004).Therefore, this KER is applicable to males mainly due to the role in testis but also to females.

References

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

Corbould, A., Bawden, M., Lavranos, T., Rodgers, R., & Judd, S. (2002). The effect of obesity on the ratio of type 3 17β-hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra-abdominal adipose tissue of women. International Journal of Obesity, 26(2), 165–175. https://doi.org/10.1038/sj.ijo.0801886

Day, J. M., Tutill, H. J., Foster, P. A., Bailey, H. V., Heaton, W. B., Sharland, C. M., Vicker, N., Potter, B. V. L., Purohit, A., & Reed, M. J. (2009). Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3. Molecular and Cellular Endocrinology, 301(1–2), 251–258. https://doi.org/10.1016/j.mce.2008.08.014

Lawrence, B. M., O’Donnell, L., Smith, L. B., & Rebourcet, D. (2022). New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice. International Journal of Molecular Sciences, 23(24), 15555. https://doi.org/10.3390/ijms232415555

Miller, W. L., & Auchus, R. J. (2019). The “backdoor pathway” of androgen synthesis in human male sexual development. PLOS Biology, 17(4), e3000198. https://doi.org/10.1371/journal.pbio.3000198

Mindnich, R., Möller, G., & Adamski, J. (2004). The role of 17 beta-hydroxysteroid dehydrogenases. Molecular and Cellular Endocrinology, 218(1–2), 7–20. https://doi.org/10.1016/j.mce.2003.12.006

Payne, A. H., & Hales, D. B. (2004). Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones. Endocrine Reviews, 25(6), 947–970. https://doi.org/10.1210/er.2003-0030

Scott, H. M., Mason, J. I., & Sharpe, R. M. (2009). Steroidogenesis in the Fetal Testis and Its Susceptibility to Disruption by Exogenous Compounds. Endocrine Reviews, 30(7), 883–925. https://doi.org/10.1210/er.2009-0016

Shima, Y., Miyabayashi, K., Haraguchi, S., Arakawa, T., Otake, H., Baba, T., Matsuzaki, S., Shishido, Y., Akiyama, H., Tachibana, T., Tsutsui, K., & Morohashi, K. (2013). Contribution of Leydig and Sertoli Cells to Testosterone Production in Mouse Fetal Testes. Molecular Endocrinology, 27(1), 63–73. https://doi.org/10.1210/me.2012-1256

Sipilä, P., Junnila, A., Hakkarainen, J., Huhtaniemi, R., Mairinoja, L., Zhang, F. P., Strauss, L., Ohlsson, C., Kotaja, N., Huhtaniemi, I., & Poutanen, M. (2020). The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency. The FASEB Journal, 34(5), 6111–6128. https://doi.org/10.1096/fj.201902384R

Spires, T. E., Fink, B. E., Kick, E. K., You, D., Rizzo, C. A., Takenaka, I., Lawrence, R. M., Ruan, Z., Salvati, M. E., Vite, G. D., Weinmann, R., Attar, R. M., Gottardis, M. M., & Lorenzi, M. V. (2005). Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3). The Prostate, 65(2), 159–170. https://doi.org/10.1002/pros.20279