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Relationship: 1498


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 Sexual behavior, decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 sexual behavior non-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
Japanese quail Coturnix japonica NCBI
Cynops pyrrhogaster Cynops pyrrhogaster NCBI

Sex Applicability

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

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

Gonadal steroid and prolactin are required to initiate a cascade of molecular events leading to sexual behavior. The cumulation of these reactions leads to the secretion of 7α-hydroxypregnenolone in the brain, a neurosteroid that acts as a trigger on sexual behavior.

7α-hydroxypregnenolone is synthesized by CYP7B in the telencephalon of both male and female. Its concentration fluctuates in the male brain according to season and light exposure, whereas it remains low in female. In agreement with the variation in 7α-hydroxypregnenolone concentration is the variation in sexual behavior frequency in male. Indeed, it was previously noted that 7α-hydroxypregnenolone peaked during the breeding period, increasing locomotor activity and frequency of tail-vibrating behavior (newt) or chasing, crowing, strutting, and mounting (bird).

Other components are required to induce sexual behavior since injection of 7α-hydroxypregnenolone in sexually immature newt has no effect on this specific parameter. However, no sexual behavior can be elicited in absence of 7α-hydroxypregnenolone.

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

It is known that 7α-hydroxypregnenolone is secreted in the diencephalon. However, the fine-tuning mechanism of its regulation is still undetermined.

In newt, the neurosteroid secretion is driven by melatonin and prolactin, an important circadian and breeding regulator, respectively (Matsunaga et al., 2004; Tsutsui et al., 2008). Prolactin is synthetized in the hypophysis and is one of the molecules required to initiate the cascade of molecular events leading to sexual behavior in newt (Kikuyama et al., 1980). In male newt, it induces a dose-dependent activation of sexual behavior. Immunofluorescence experiments conducted on newt brain sections revealed the presence of prolactin receptors on neurons expressing CYP7B, which could explain the direct correlation between prolactin and 7α-hydroxypregnenolone secretion in relation to sexual behavior.

Quail are highly sensitive to light exposure and their behavior mostly relies on circadian rhythm. Melatonin secretion, high during the night, is known to inhibit CYP7B activity in male brain, which, in turn, decreases 7α-hydroxypregnenolone concentration. Following the same pattern, sexual behavior in male quail is high during the day and significiantly lower at night.

A decrease in sexual behavior can be induced by steroid hormones deregulation since their involvement in the regulation of sexual behavior is prominent. Indeed, castration of male bird induces a decrease/loss of reproductive behavior, which can be rescued by a testosterone therapy (Adkins and Adler, 1972). The same effect can be induced in bird by transferring them from a 16-hr.-light 8-hr.-dark cycle to an 8-hr.- light 16-hr.-dark cycle, which demonstrates the photoperiodic regulation of sexual behavior in bird (Sach, 1967). 

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

Courtship and sexual behavior is due to the synergistic effect of multiple hormones (Iwata et al., 2000). 7α-hydroxypregnenolone is one of them and it was shown to be essential for sexual behavior, but it is not sufficient in itself to trigger sexual behavior in absence of prolactin (secreted in sexually mature animals during the breeding season).  

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
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


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

Kikuyama, S., Yamamoto, K., Seki T. (1980). Prolactin and its role in growth, metamorphosis and reproduction in amphibians, Gunma Symp. Endocrinol., 17, 3–13

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.