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Relationship: 3522

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 Decreased, Progesterone levels

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

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

This key event relationship describes decreased levels of pregnenolone that causes a decrease in progesterone levels.

Pregnenolone is the precursor to all steroid hormones and is the direct precursor to progesterone. Progesterone is synthesized from the conversion of pregnenolone by 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) (Bremer & Miller, 2014; Kamrath et al., 2014). Therefore, a decrease in the levels of pregnenolone can negatively impact the levels of progesterone through a lack of substrate for the enzymatic reaction. A decrease in pregnenolone can happen through multiple mechanisms: pregnolone can be converted to 17-OH pregnenolone, it can be sulfated to pregnenolone-S (Bremer & Miller, 2014; V et al., 2018), and the upstream reactions leading to pregnenolone synthesis may be affected. Interference with any of these processes can lead to decreased pregnenolone levels, which again may decrease progesterone 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 chapter that summarise the canonical knowledge. PubMed was searched using key words related to steroidogenesis.

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 is well established that the synthesis and presence of pregnenolone is necessary for progesterone synthesis.

The conversion of pregnenolone to progesterone occurs in several different tissues and in a species specific way by the 3-beta-HSD enzyme (Q et al., 2019). It takes place in the ovaries where pregnenolone is converted to progesterone from granulosa cells into the corpus luteum (Bremer & Miller, 2014). This conversion also occurs in the adrenal cortex and in Leydig cells primarly in rats and mice to produce androgens (Bremer & Miller, 2014; S et al., 2021; WL, 2017).

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

Since pregnenolone is a precursor to all steroid hormones, inhibiting its production should have an impact on all downstream hormone levels.

This was shown in a study using a specific inhibitor of CYP11A1, the enzyme responsible for the conversion of cholesterol to pregnenolone. The small molecule, named ODM-208, successfully inhibited CYP11A1 which resulted in drastic decrease in pregnenolone levels in H295R cells at 100 nM. At this same concentration, progesterone and other downstream hormones, decreased production to below detection level (Karimaa et al., 2022).

Using a short-term diabetes model in Wistar rats, another study demonstrated the link between the decrease of pregnenolone in the kidneys with reduced progesterone levels. By administering streptozotocin (STZ), the rats presented symptoms of early diabetes. When inspecting protein levels, a clear decrease in CYP11A1 expression was observed in kidney tissues. This was reflected in the decrease of renal pregnenolone and subsequently, a decrease in progesterone levels. However, expression of 3-beta-HSD was not evaluated and therefore can not be excluded as playing a part in the progesterone decrease (Pagotto et al., 2021).

Cocaine exposure prenatally in rats also impacted the levels of both maternal and fetal pregnenolone and progesterone. The exposure to cocaine was executed during the third trimester twice daily (15 mg/kg/day). It had no impact on placental 3-beta-HSD1 expression but decreased expression of the mRNA and protein CYP11A (Wu et al., 2012).

Association between decreased pregnenolone and progesterone levels is observed in different species and life stages. For example, aged female rats and male rats have decreased levels of pregnenolone and progesterone compared to younger female rats (Gaignard et al., 2015). Another link between the two is seen in healthy neonatal foals, where at birth they contain high levels of plasma steroid hormones which then decrease after 48 hours. Pregnenolone and progesterone decrease drastically within 24h after birth (Aleman et al., 2019).

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

Pregnenolone is converted to 17-OH pregnenolone preferentially in humans (Kamrath et al., 2014).

Progesterone itself can reduce pregnenolone (Yuan et al., 2019).

Progesterone levels also depends on the activity of the enzyme 3-beta-HSD (Q et al., 2019).

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

Both pregnenolone and progesterone synthesis and regulation is conserved in mammals (Baker, 2011; DM et al., 2017).

Life stage applicability

This KER is applicable to all life stages as both hormones are essential (Baker, 2011; Bremer & Miller, 2014; DM et al., 2017).

Sex applicability

Pregnenolone and progesterone are expressed and important in males and females (Baker, 2011; Bremer & Miller, 2014).

References

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

Aleman, M., McCue, P. M., Chigerwe, M., & Madigan, J. E. (2019). Plasma concentrations of steroid precursors, steroids, neuroactive steroids, and neurosteroids in healthy neonatal foals from birth to 7 days of age. Journal of Veterinary Internal Medicine, 33(5), 2286–2293. https://doi.org/10.1111/jvim.15618

Baker, M. E. (2011). Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Molecular and Cellular Endocrinology, 334(1–2), 14–20. https://doi.org/10.1016/j.mce.2010.07.013

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

DM, S., AH, Z., LN, T., K, M., & V, S. (2017). A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis. Molecular and Cellular Endocrinology, 441, 7–16. https://doi.org/10.1016/j.mce.2016.07.036

Gaignard, P., Savouroux, S., Liere, P., Pianos, A., Thérond, P., Schumacher, M., Slama, A., & Guennoun, R. (2015). Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice. Endocrinology, 156(8), 2893–2904. https://doi.org/10.1210/en.2014-1913

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

Karimaa, M., Riikonen, R., Kettunen, H., Taavitsainen, P., Ramela, M., Chrusciel, M., Karlsson, S., Rummakko, P., Simola, O., Wohlfahrt, G., Hakulinen, P., Vuorela, A., Joensuu, H., Utriainen, T., Fizazi, K., & Oksala, R. (2022). First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis. Molecular Cancer Therapeutics, 21(12), 1765–1776. https://doi.org/10.1158/1535-7163.MCT-22-0115

Pagotto, M. A., Roldán, M. L., Molinas, S. M., Raices, T., Pisani, G. B., Pignataro, O. P., & Monasterolo, L. A. (2021). Impairment of renal steroidogenesis at the onset of diabetes. Molecular and Cellular Endocrinology, 524, 111170. https://doi.org/10.1016/j.mce.2021.111170

Q, Z., P, P., X, C., Y, W., S, Z., J, M., X, L., & RS, G. (2019). Human placental 3β-hydroxysteroid dehydrogenase/steroid Δ5,4-isomerase 1: Identity, regulation and environmental inhibitors. Toxicology, 425, 152253. https://doi.org/10.1016/j.tox.2019.152253

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

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

Wu, L., Yan, J., Qu, S. C., Feng, Y. Q., & Jiang, X. L. (2012). Abnormal regulation for progesterone production in placenta with prenatal cocaine exposure in rats. Placenta, 33(12), 977–981. https://doi.org/10.1016/j.placenta.2012.10.001

Yuan, X., Yang, C., Wang, X., Zhang, L., Gao, X., & Shi, Z. (2019). Progesterone maintains the status of granulosa cells and slows follicle development partly through PGRMC1. Journal of Cellular Physiology, 234(1), 709–720. https://doi.org/10.1002/jcp.26869