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Relationship: 1493

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

CYP7B activity, inhibition leads to 7α-hydroxypregnenolone synthesis in the brain, decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
CYP7B activity, inhibition
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
7α-hydroxypregnenolone synthesis 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 High Moderate Brendan Ferreri-Hanberry (send email) Not under active development
Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior adjacent Arthur Author (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
Japanese quail Coturnix japonica NCBI

Sex Applicability

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

Life Stage Applicability

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

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

Neurosteroids are steroids synthesized in the brain that interact with cell surface receptors or ligand-gated ion channels in order to modify the neuronal excitability (Paul and Purdy, 1992). They are involved in numerous biological functions including locomotor activity, memory, learning, sexually-dimorphic behaviors and anxiety.

Neurosteroids are synthesized from pregnenolone or its derivatives by different cytochromes P450. Among these CYPs is CYP7B hydroxylase which synthesizes the neurosteroid 7α-hydroxypregnenolone. CYP7B is the only enzyme responsible for the synthesis of this neurosteroid. Therefore, its inhibition induces a decrease in 7α-hydroxypregnenolone concentration in the brain.

The expression of CYP7B and the synthesis of its molecular product vary cyclically on a daily and/or seasonal basis. In male quail, a diurnal animal, CYP7B expression and 7α-hydroxypregnenolone are inhibited by melatonin secretion, a hormone involved in circadian rhythm and sleep regulation. Oppositely, in a nocturnal animal such a newt, melatonin acts as an inducer of CYP7B expression and 7α-hydroxypregnenolone synthesis. These results indicate that CYP7B expression and therefore 7α-hydroxypregnenolone synthesis follow a circadian rhythm regulation.  

In addition to this daily variation, CYP7B and its product are regulated by seasons in salmon and male newt where it peaks during homing migration (salmon) and breeding (newt) period (Haraguchi et al., 2009). It is plausible that the same seasonal variation occurs in avian.

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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

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

The vertebrate brain expresses all the enzymes involved in the different steroidogenic pathways (do Rego and Vaudry, 2016; Tsutsui et al., 1999).

The physiological function of 7α-hydroxypregnenolone is more understood in birds, newts, and rats than in human. However, the direct causal effect between CYP7B inhibition and the decrease in 7α-hydroxyPREG was demonstrated in human, fish and other vertebrates (Haraguchi et al., 2015; Yantsevich et al., 2014; Yau et al., 2006). 

Therefore, it is plausible that this KER is applicable to all vertebrates.