This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3516

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased 3βHSD activity leads to Decreased, Progesterone levels

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased 3βHSD activity

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Progesterone levels

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

3-beta-Hydroxysteroid dehydrogenase (3-beta-HSD) is a crucial enzyme in the steroidogenesis pathway, responsible for converting hydroxysteroids to ketosteroids like pregnenolone to progesterone in this KER. Decreased enzyme activity will directly lead to decreased progesterone levels among other steroids. This KER currently focuses on the 3-beta-HSD enzyme activity and does not include expression levels.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The KER describes a generally recognized and understood process, i.e. canonical knowledge. The aim of the literature search was therefore to identify review articles and book chapters that summarise the canonical knowledge. PubMed was searched using key words related to steroidogenesis. The search was restricted to reviews from the last 10 years.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

3-beta-HSD is a critical enzyme in the steroidogenic pathway, responsible for catalysing an essential step in the synthesis of progesterone from pregnenolone. Any effect on 3-beta-HSD disrupts this conversion, leading to a reduction in progesterone levels.

The role of 3-beta-HSD in steroidogenesis becomes evident in individuals with 3-beta-HSD deficiency. These individuals have congenital adrenal hyperplasia (CAH), characterized by a severe impairment of steroid biosynthesis indicated by high levels of pregnenolone but low levels of progesterone and downstream hormones (Donadille et al., 2018).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical evidence is provided in Table 1, where studies presented demonstrate reduced conversion of pregnenolone to progesterone upon 3-beta-HSD inhibition. Most studies presented have assessed the endpoints in male systems with only one study on female, being luteal cells. Several studies have exposed the system to perfluoroalkyl substances (PFOA, PFOS, PFOSK). The potency of 3-beta-HSD inhibition by perfluoroalkyl substances has been shown to depend on the length of the carbon chain, with at least 8 carbons required for inhibition (Zhao et al., 2010b).

Table 1. Studies contributing to empirical evidence where reduced conversion of pregnenolone to progesterone was observed.

Test system	Compound	IC₅₀	Reference
Testicular microsome from 90 d.o. Sprague Dawley rats	PFOA	53 μM	(Zhao et al., 2010a)
Testicular microsome from 90 d.o. Sprague Dawley rats	PFOA, PFOS, PFOSK	53.2, 1.3, 1.7 μΜ	(Zhao et al., 2010b)
Testicular microsome from humans	PFOA, PFOS, PFOSK	>250 μM	(Zhao et al., 2010b)
Testicular microsome from 90 d.o. Sprague Dawley rats	BPA	26.4 μM	(Ye et al., 2011)
Testicular microsome from humans	BPA	7.9 μM	(Ye et al., 2011)
Testicular microsome from Sprague Dawley rats	MXC, HPTE	46.1, 13.8 μM	(Hu et al., 2011)
Testicular microsome from humans	MXC, HPTE	53.2, 8.2 μM	(Hu et al., 2011)
Testicular microsome from Sprague Dawley rats	Genistein	636 nM	(Hu et al., 2010)
Testicular microsome from humans	Genistein	87 nM	(Hu et al., 2010)
Isolated bovine luteal cells	Gossypol	Effect concentrations: 17, 34 μΜ	(Gu et al., 1990)
Testicular microsome from 90 d.o. Sprague Dawley rats	(+)-gossypol, (-)-gossypol	0.19, 0.23 μΜ	(Hu et al., 2009)
Testicular microsome from humans	(+)-gossypol, (-)-gossypol	4.45, 2.77 μΜ	(Hu et al., 2009)
7-day oral exposure of Sprague Dawley rats	(+)-gossypol, (-)-gossypol	Effect dose: 20mg/kg/day	(Hu et al., 2009)
Testicular microsome from Sprague Dawley rats	DPrP, DBP, DPP, BBOP, DCHP	62.7, 30.3, 33.8, 82.6, and 24.7 μM	(Yuan et al., 2012)
Testicular microsome from humans	DPrP, DBP, DPP, BBOP, DCHP	123.0, 24.1, 25.5, 50.3, and 25.5 μM	(Yuan et al., 2012)
Testicular microsome from 35 d.o. Sprague Dawley rats	BHA	50 μM	(Li et al., 2016)
3h exposure of isolated Leydig cells from 35 d.o. Sprague Dawley rats	BHA	50 μM	(Li et al., 2016)
Testicular microsome from 35 d.o. Sprague Dawley rats	Resveratrol	3.87 μM	(Li et al., 2014)
Testicular microsome from humans	Resveratrol	8.48 μM	(Li et al., 2014)
Testicular microsome from 35 d.o. Sprague Dawley rats	Apigenin	2.17 μM	(Wang et al., 2016)
Testicular microsome from humans	Apigenin	11.41 μM	(Wang et al., 2016)
Testicular microsome from 35 d.o. Sprague Dawley rats	Etomidate	9.16 μM	(Liu et al., 2015)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Genotype is a modulating factor of this KER, with 37 known mutations in the HSD3B2 gene affecting the efficiency of the enzyme (Simard et al., 2005).

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

The catalytic products of 3β-HSD inhibit its enzymatic activity (Nguyen et al., 2012).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

3-beta-HSD is essential for steroidogenesis, catalyzing the production of progesterone and other steroids in vertebrates, with this KER focusing on mammals. Different 3-beta-HSD isoforms display tissue-specific expression and function from fetal life to adulthood in both sexes, ensuring progesterone production across these life stages (Rasmussen et al., 2013). In females, progesterone is crucial for the menstrual/estrous cycle and pregnancy, with primary sites of production being the placenta and corpus luteum and in males it serves as a precursor for androgens and corticosteroids.

References

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

Donadille, B., Houang, M., Netchine, I., Siffroi, J.P., Christin-Maitre, S., 2018. Human 3beta-hydroxysteroid dehydrogenase deficiency associated with normal spermatic numeration despite a severe enzyme deficit. Endocr Connect 7, 395–402. https://doi.org/10.1530/EC-17-0306

Gu, Y., Lin, Y.C., Rikihisa, Y., 1990. INHIBITORY EFFECT OF GOSSYPOL ON STEROIDOGENIC PATHWAYS IN CULTURED BOVINE LUTEAL CELLS.

Hu, G.X., Zhao, B., Chu, Y., Li, X.H., Akingbemi, B.T., Zheng, Z.Q., Ge, R.S., 2011. Effects of methoxychlor and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase-3 activities in human and rat testes. Int J Androl 34, 138–144. https://doi.org/10.1111/j.1365-2605.2010.01065.x

Hu, G.X., Zhao, B.H., Chu, Y.H., Zhou, H.Y., Akingbemi, B.T., Zheng, Z.Q., Ge, R.S., 2010. Effects of genistein and equol on human and rat testicular 3Β-hydroxysteroid dehydrogenase and 17Β-hydroxysteroid dehydrogenase 3 activities. Asian J Androl 12, 519–526. https://doi.org/10.1038/aja.2010.18

Hu, G.X., Zhou, H.Y., Li, X.W., Chen, B.B., Xiao, Y.C., Lian, Q.Q., Liang, G., Kim, H.H., Zheng, Z.Q., Hardy, D.O., Ge, R.S., 2009. The (+)- and (-)-gossypols potently inhibit both 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 in human and rat testes. Journal of Steroid Biochemistry and Molecular Biology 115, 14–19. https://doi.org/10.1016/j.jsbmb.2009.02.004

Li, L., Chen, X., Zhu, Q., Chen, D., Guo, J., Yao, W., Dong, Y., Wei, J., Lian, Q., Ge, R.S., Yuan, B., 2014. Disrupting androgen production of Leydig cells by resveratrol via direct inhibition of human and rat 3β-hydroxysteroid dehydrogenase. Toxicol Lett 226, 14–19. https://doi.org/10.1016/j.toxlet.2014.01.022

Li, X., Cao, S., Mao, B., Bai, Y., Chen, X., Wang, X., Wu, Y., Li, L., Lin, H., Lian, Q., Huang, P., Ge, R.S., 2016. Effects of butylated hydroxyanisole on the steroidogenesis of rat immature Leydig cells. Toxicol Mech Methods 26, 511–519. https://doi.org/10.1080/15376516.2016.1202367

Liu, H.C., Zhu, D., Wang, C., Guan, H., Li, S., Hu, C., Chen, Z., Hu, Y., Lin, H., Lian, Q.Q., Ge, R.S., 2015. Effects of etomidate on the steroidogenesis of rat immature leydig cells. PLoS One 10. https://doi.org/10.1371/journal.pone.0139311

Nguyen, P.T.T., Lee, R.S.F., Conley, A.J., Sneyd, J., Soboleva, T.K., 2012. Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis. Journal of Steroid Biochemistry and Molecular Biology 128, 12–20. https://doi.org/10.1016/j.jsbmb.2011.10.003

Rasmussen, M.K., Ekstr, B., Zamaratskaia, G., 2013. Regulation of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase: A review. Int J Mol Sci. https://doi.org/10.3390/ijms140917926

Simard, J., Ricketts, M.L., Gingras, S., Soucy, P., Feltus, F.A., Melner, M.H., 2005. Molecular biology of the 3β-hydroxysteroid dehydrogenase/ Δ5-Δ4 isomerase gene family. Endocr Rev. https://doi.org/10.1210/er.2002-0050

Wang, X., Wang, G., Li, X., Liu, J., Hong, T., Zhu, Q., Huang, P., Ge, R.S., 2016. Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer. Fitoterapia 111, 66–72. https://doi.org/10.1016/j.fitote.2016.04.014

Ye, L., Zhao, B., Hu, G., Chu, Y., Ge, R.S., 2011. Inhibition of human and rat testicular steroidogenic enzyme activities by bisphenol A. Toxicol Lett 207, 137–142. https://doi.org/10.1016/j.toxlet.2011.09.001

Yuan, K., Zhao, B., Li, X.W., Hu, G.X., Su, Y., Chu, Y., Akingbemi, B.T., Lian, Q.Q., Ge, R.S., 2012. Effects of phthalates on 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities in human and rat testes. Chem Biol Interact 195, 180–188. https://doi.org/10.1016/j.cbi.2011.12.008

Zhao, B., Chu, Y., Hardy, D.O., Li, X. kun, Ge, R.S., 2010a. Inhibition of 3β- and 17β-hydroxysteroid dehydrogenase activities in rat Leydig cells by perfluorooctane acid. Journal of Steroid Biochemistry and Molecular Biology 118, 13–17. https://doi.org/10.1016/j.jsbmb.2009.09.010

Zhao, B., Hu, G.X., Chu, Y., Jin, X., Gong, S., Akingbemi, B.T., Zhang, Z., Zirkin, B.R., Ge, R.S., 2010b. Inhibition of human and rat 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities by perfluoroalkylated substances. Chem Biol Interact 188, 38–43. https://doi.org/10.1016/j.cbi.2010.07.001