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Relationship: 1878

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

Inhibition of Cyp17A1 activity leads to Reduction, DHEA

Upstream event

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

Inhibition of Cyp17A1 activity

Downstream event

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

Reduction, DHEA

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

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)	adjacent	High		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 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

This key event relationship (KER) links inhibition of CYP17A1 activity to decreased dehydroepiandrosterone (DHEA) levels.

CYP17A1 plays a dual role in DHEA synthesis, as is performs both a 17α-hydroxylation and 17,20-lyase transformation. This leads to the transformation of pregnenolone to 17-OH-pregnenolone and 17-OH-pregnenolone to DHEA, respectively (Burris-Hiday & Scott, 2021; Miller & Auchus, 2011, 2019; Peng et al., 2019; Wróbel et al., 2023). If either of these reactions are inhibited, it can lead to decreased DHEA 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

The biological plausibility of this KER is considered high.

The CYP17A1 enzyme facilitates two reactions in the process of DHEA synthesis. A 17α-hydroxylase reaction that converts pregnenolone to 17-OH-pregnenolone and a 17,20-lyase reaction that converts 17-OH-pregnenolone to DHEA. The 17α-hydroxylase reactions take place at the C17 of pregnenolone, whereas the lyase reaction leads to a breakage between the C17 and C20 of 17-OH-pregnenolone. Both reactions are dependent on the cofactor P450 oxidoreductase, where the lyase reaction is also dependent on the cofactor cytochrome B5 (Burris-Hiday & Scott, 2021; Miller & Auchus, 2011, 2019; Peng et al., 2019; Wróbel et al., 2023).

CYP17A1 is expressed in the testis, ovary, adrenal, but also in the placenta, heart, adipose, liver, brain, and kidney tissue depending on species (Zirkin & Papadopoulos, 2018). Specifically, CYP17A1 is expressed in the testicular Leydig cells, in the ovarian Theca cells and in the zona reticularis and zona fasciculate of the adrenal gland (Chatuphonprasert et al., 2018; Odermatt et al., 2016; Peng et al., 2019; Petrunak et al., 2014; Storbeck et al., 2011; Wróbel et al., 2023).

The lyase reaction leading to DHEA from 17-OH-pregnenolone is dominant in humans and primates compared to rodents (Lawrence et al., 2022; Miller & Auchus, 2011).

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

A major empirical evidence came from CYP17 knock down cell studies. In 2005, Liu Y., Yao ZX., and Papadopoulos V. showed that MA-10 CYP17 knock down cells synthesize much less pregnenolone and DHEA compared with MA-10 wild type cells. In this study, de novo endogenous cholesterol synthesis was blocked with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. After cells incubation with a radiolabeled cholesterol precursor ([3H]mevalonactone), progesterone and DHEA were fractionned using HPLC and identify using standards. After quantification by liquid scintillation spectrometry, results indicated that the MA-10CYP17KD cells synthesize much less pregnenolone, progesterone and DHEA. These results enable to highlight the important factor of CYP17a1 in 17-OH-pregnenolone conversion to DHEA.

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

The mentioned study is based on MA-10 mouse tumor Leydig cells. Even though mouse is the prefered animal model for reproductive studies, a human-cell based study would be stronger.

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

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

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

This KE is applicable for both sexes, across developmental stages into adulthood, and across mammalian taxa.

References

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

Burris-Hiday, S. D., & Scott, E. E. (2021). Steroidogenic cytochrome P450 17A1 structure and function. Molecular and Cellular Endocrinology, 528. https://doi.org/10.1016/j.mce.2021.111261

Chatuphonprasert, W., Jarukamjorn, K., & Ellinger, I. (2018). Physiology and pathophysiology of steroid biosynthesis, transport and metabolism in the human placenta. In Frontiers in Pharmacology (Vol. 9, Issue SEP). Frontiers Media S.A. https://doi.org/10.3389/fphar.2018.01027

Lawrence, B. M., O’Donnell, L., Smith, L. B., & Rebourcet, D. (2022). New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice. In International Journal of Molecular Sciences (Vol. 23, Issue 24). MDPI. https://doi.org/10.3390/ijms232415555 Miller, W. L., & Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 32(1), 81–151. https://doi.org/10.1210/er.2010-0013

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

Odermatt, A., Strajhar, P., & Engeli, R. T. (2016). Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools. In Journal of Steroid Biochemistry and Molecular Biology (Vol. 158, pp. 9–21). Elsevier Ltd. https://doi.org/10.1016/j.jsbmb.2016.01.009

Peng, Z., Xueb, G., Chen, W., & Xia, S. (2019). Environmental inhibitors of the expression of cytochrome P450 17A1 in mammals. In Environmental Toxicology and Pharmacology (Vol. 69, pp. 16–25). Elsevier B.V. https://doi.org/10.1016/j.etap.2019.02.007

Petrunak, E. M., DeVore, N. M., Porubsky, P. R., & Scott, E. E. (2014). Structures of human steroidogenic cytochrome P450 17A1 with substrates. Journal of Biological Chemistry, 289(47), 32952–32964. https://doi.org/10.1074/jbc.M114.610998

Storbeck, K. H., Swart, P., Africander, D., Conradie, R., Louw, R., & Swart, A. C. (2011). 16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction. In Molecular and Cellular Endocrinology (Vol. 336, Issues 1–2, pp. 92–101). https://doi.org/10.1016/j.mce.2010.11.016

Wróbel, T. M., Jørgensen, F. S., Pandey, A. V., Grudzińska, A., Sharma, K., Yakubu, J., & Björkling, F. (2023). Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment. In Journal of Medicinal Chemistry (Vol. 66, Issue 10, pp. 6542–6566). American Chemical Society. https://doi.org/10.1021/acs.jmedchem.3c00442

Zirkin, B. R., & Papadopoulos, V. (2018). Leydig cells: Formation, function, and regulation. In Biology of Reproduction (Vol. 99, Issue 1, pp. 101–111). Oxford University Press. https://doi.org/10.1093/biolre/ioy059