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Relationship: 3520

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, Pregnenolone levels leads to Reduction, DHEA

Upstream event

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

Decreased, Pregnenolone levels

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

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 describes the relation between decreased levels of pregnenolone causing a decrease in dehydroepiandrosterone (DHEA) levels. As pregnenolone is the precursor to steroidogenesis hormones, it-stands to reason that decrease in its levels would impact downstream hormones such as DHEA. Pregnenolone is converted into DHEA through a couple intermediary steps; it is converted into 17-OH-pregnenolone which can then be synthesized into DHEA (Bremer & Miller, 2014; WL, 2017).

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

It’s well established that pregnenolone is a necessary precursor for DHEA synthesis (Bremer & Miller, 2014; WL, 2017).

Human Leydig cells produce DHEA through the conversion of pregnenolone via 17-OH-pregnenolone by the enzyme CYP17A1 (FK & RJ, 2015). This is the main pathway in humans known as the Δ5 pathway. The production of DHEA allows its further conversion to other potent androgens, testosterone and DHT. In theca cells as well as the adrenals, pregnenolone is also converted to DHEA to produce androgens and finally estrogens in the granulosa cells (Kamrath et al., 2014; S et al., 2021; V et al., 2018; WL, 2017; Z et al., 2019).

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

Exposure to different stressors can lead to a decrease of pregnenolone that in turn leads to decrease of downstream hormones like DHEA.

Using H295R cells, 72h exposure of 1μM of ketoconazole decreased significantly the levels of pregnenolone and DHEA (Nielsen et al., 2012). This was also observed using another fungicide fluconazole on both H295R cells and its clonal cell line, HAC15 (van der Pas et al., 2012).

Pomegranate extracts are being investigated for possible cancer treatment. Using two prostate cancer cell lines (22RV1 and LNCaP), a study focused on the effect of pomegranate extracts on steroid biosynthesis. They observed that pomegranate extracts reduced the levels of pregnenolone and androgens including specifically DHEA. PTEN KO mice fed pomegranate extracts (0.17 g/L in drinking water) confirmed the in vitro results with a significant decrease in pregnenolone (36.5% compared to control) and DHEA (42.1%) (Ming et al., 2014).

Cigarette smoke was also shown to reduce certain steroid hormone levels in mice. Specifically, both pregnenolone and DHEA levels decreased in ovarian tissue (Pawlak et al., 2011).

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

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

Taxonomic applicability

DHEA is favourably synthesized from pregnenolone in human, primates, cats, bovine, sheep and goats through the Δ5 pathway (Lawrence et al., 2022). This KER is applicable to mammals.

Life stage applicability

DHEA is synthesized in the fetus and adult (Chatuphonprasert et al., 2018; Miller & Auchus, 2011).

Sex applicability

Both pregnenolone and DHEA are essential hormones in both males and females as precursor of androgens (Bremer & Miller, 2014; Kamrath et al., 2014; V et al., 2018).

References

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

Bremer, A. A., & Miller, W. L. (2014). Regulation of Steroidogenesis. In Cellular Endocrinology in Health and Disease (pp. 207–227). Elsevier. https://doi.org/10.1016/B978-0-12-408134-5.00013-5

Chatuphonprasert, W., Jarukamjorn, K., & Ellinger, I. (2018). Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.01027

FK, Y., & RJ, A. (2015). The diverse chemistry of cytochrome P450 17A1 (P450c17, CYP17A1). The Journal of Steroid Biochemistry and Molecular Biology, 151, 52–65. https://doi.org/10.1016/j.jsbmb.2014.11.026

Kamrath, C., Wudy, S. A., & Krone, N. (2014). Steroid Biochemistry (pp. 41–52). https://doi.org/10.1159/000363612

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. (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

Ming, D.-S., Pham, S., Deb, S., Chin, M. Y., Kharmate, G., Adomat, H., Beheshti, E. H., Locke, J., & Guns, E. T. (2014). Pomegranate extracts impact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo. The Journal of Steroid Biochemistry and Molecular Biology, 143, 19–28. https://doi.org/10.1016/j.jsbmb.2014.02.006

Nielsen, F. K., Hansen, C. H., Fey, J. A., Hansen, M., Jacobsen, N. W., Halling-Sørensen, B., Björklund, E., & Styrishave, B. (2012). H295R cells as a model for steroidogenic disruption: A broader perspective using simultaneous chemical analysis of 7 key steroid hormones. Toxicology in Vitro, 26(2), 343–350. https://doi.org/10.1016/j.tiv.2011.12.008

Pawlak, K. J., Prasad, M., McKenzie, K. A., Wiebe, J. P., Gairola, C. G., Whittal, R. M., & Bose, H. S. (2011). Decreased Cytochrome c Oxidase IV Expression Reduces Steroidogenesis. Journal of Pharmacology and Experimental Therapeutics, 338(2), 598–604. https://doi.org/10.1124/jpet.111.182634

S, C.-P., T, L., P, L., C, D.-L., A, D., PA, F., & S, M.-G. (2021). Six Decades of Research on Human Fetal Gonadal Steroids. International Journal of Molecular Sciences, 22(13). https://doi.org/10.3390/ijms22136681

V, S., DM, S., & BJ, C. (2018). Current knowledge on the acute regulation of steroidogenesis. Biology of Reproduction, 99(1), 13–26. https://doi.org/10.1093/biolre/ioy102

van der Pas, R., Hofland, L. J., Hofland, J., Taylor, A. E., Arlt, W., Steenbergen, J., van Koetsveld, P. M., de Herder, W. W., de Jong, F. H., & Feelders, R. A. (2012). Fluconazole inhibits human adrenocortical steroidogenesis in vitro. Journal of Endocrinology, 215(3), 403–412. https://doi.org/10.1530/JOE-12-0310

WL, M. (2017). Steroidogenesis: Unanswered Questions. Trends in Endocrinology and Metabolism: TEM, 28(11), 771–793. https://doi.org/10.1016/j.tem.2017.09.002

Z, P., G, X., W, C., & S, X. (2019). Environmental inhibitors of the expression of cytochrome P450 17A1 in mammals. Environmental Toxicology and Pharmacology, 69, 16–25. https://doi.org/10.1016/j.etap.2019.02.007