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Relationship: 1496

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

7α-hydroxypregnenolone synthesis in the brain, decreased leads to Dopamine release in the brain, decreased

Upstream event

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

7α-hydroxypregnenolone synthesis in the brain, decreased

Downstream event

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

Dopamine release in the brain, decreased

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 CYP7B activity leads to decreased reproductive success via decreased locomotor activity	adjacent	Low	Low	Florence Pagé-Larivière (send email)	Not under active development
Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior	adjacent			Florence Pagé-Larivière (send email)	Not under active development

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
Cynops pyrrhogaster	Cynops pyrrhogaster		NCBI

Sex Applicability

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

Sex	Evidence
Male	Moderate

Life Stage Applicability

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

Term	Evidence
Adult, reproductively mature

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

7α-hydroxypregnenolone is synthesized in the diencephalon and the rhombencephalon (newt only) and has a paracrine effect on dopaminergic neurons that project into the telencephalon including the striatum.

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

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

7α-hydroxypregnenolone cannot be directly related to dopamine release since it has no known receptor and the cells that synthesize it are not in direct contact with the dopaminergic neurons. However, it was shown that 7α-hydroxypregnenolone release induces dopamine secretion in the brain.

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

7α-hydroxypregnenolone concentration in the brain of salmon prior to upstream migration was decreased using aminoglutethimide (AG) injection (CYP11A inhibitor) and lead to a decreased dopamine concentration in the telencephalon compared to control. This effect was rescued with intracerebroventricular injection of 7α-hydroxypregnenolone. Simultaneous measurements of hypothalamic dopamine concentration showed an absence of variation after AG-injection or AG+7 PREG (Haraguchi et al., 2015)

Tyrosine hydroxylase (TH) is a marker of dopamine neurons. Immunolabelling of CYP7B and TH revealed that these enzymes are expressed in two different cell populations in the salmon magnocellular preoptic nucleus and that they are in close proximity to each other (Haraguchi et al., 2015).

7α-hydroxypregnenolone (1 ng) was injected in non-breeding male newt and several monoamines concentration were measured using HPLC-electrochemical detection. 7α-hydroxypregnenolone increased dopamine concentration in the rostral brain region including striatum. No change was observed in the concentration of any other monoamine (Matsunaga et al., 2004).

Newt brain incubated in vitro with 7α-hydroxypregnenolone (0, 10⁻⁸, 10⁻⁷, or 10⁻⁶ M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004).

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

Since the neurosteroid receptor has yet to be identified, no direct interaction between 7α-hydroxypregnenolone and dopaminergic neuron has been demonstrated. It is thus possible that an intermediate event takes place in between to indirectly connect the neurosteroid to dopamine release.

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

One study specifically performed a dose-reponse experiment for 7α-hydroxypregnenolone in relation to dopamine concentration.

Newt brain incubated with 7α-hydroxypregnenolone (0, 10⁻⁸, 10⁻⁷, or 10⁻⁶ M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004).

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

References

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

Haraguchi, S., Yamamoto, Y., Suzuki, Y., Hyung Chang, J., Koyama, T., Sato, M., Mita, M., Ueda, H., and Tsutsui, K. (2015). 7alpha-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon. Sci Rep 5, 12546.

Matsunaga, M., Ukena, K., Baulieu, E.E., and Tsutsui, K. (2004). 7alpha-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system. Proc Natl Acad Sci U S A 101, 17282-17287.