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Relationship: 1494

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 Locomotor activity, 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

Locomotor activity, 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	non-adjacent	Low	Low	Brendan Ferreri-Hanberry (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
Male

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

CYP7B is expressed in the mammalian brain where it catalyzes synthesis of 7α-hydroxypregnenolone, among other neurosteroids. However, it governs spatial memory and learning rather than locomotor activity. Thus, although CYP7B and 7α-hydroxypregnenolone are present in the brain of vertebrates, there functions are different in mammals and non-mammals.

The importance of CYP7B neurosteroid synthesis is sex dependent in bird and newt. In these species, only male locomotor activity is influenced by CYP7B expression. However, both male and female are affected by CYP7B activity in salmon.

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

The relationship between CYP7B and locomotor activity is clearly established is quail, newt and salmon. However, the regulation of CYP7B differs in these species.

In diurnal bird such as quail, melatonin secretion during nighttime inhibits CYP7B activity which is reflected by the decreased locomotor activity. Under daylight condition, melatonin secretion is abolished which induces an upregulation of CYP7B and an increase in locomotor activity (Tsutsui et al., 2008).

Oppositely, newt is a nocturnal animal and melatonin secretion acts as an inducer of CYP7B activity. Consequently, CYP7B activity is elevated at night and drives locomotor activity (Koyama et al., 2009).

CYP7B activity is also dependent on the peptide hormone prolactin secreted by the adenohypophysis, at least in male newt. Prolactin is a neuropeptide which secretion varies according to season. In newt, breeding season is characterized by an elevation of locomotor activity which correlates with a peak in brain prolactin concentration.

It is plausible that prolactin induces the same increase in locomotor activity in salmon during homing migration. During this period, both prolactin and CYP7B (7α-hydroxypregnenolone) are known to peak (Haraguchi et al., 2015; Onuma et al., 2010).

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

Conazoles are known to cross the blood brain barrier.
The activity of CYP7B is inhibited by conazoles (Matsunaga et al., 2004; Tsutsui et al., 2008).
Exposure to ketoconazole inhibited CYP7B activity (decreased 7α-hydroxypregnenolone concentration) and decreased locomotor activity in male quail and newt.
Depletion of CYP7B substrate (pregnenolone) with intracranial injection of aminoglutethimide (CYPscc inhibitor) decreased locomotor activity in salmon (Haraguchi et al., 2015).
Penguins treated with voriconazole (6 µg/ml of blood) became lethargic and weak. The side effects dissipated or resolved with discontinuation or dose reduction of voriconazole (Hyatt et al., 2015).

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

Conazoles are known to inhibit a variety of CYPs. Thus, when an animal is exposed to a chemical of this family, multiple enzymatic targets are likely to be affected. It is plausible that the impacts of the exposure are the result of multiple CYPs inhibition that all converge toward the same phenotype.

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

No information is available at this moment.

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

CYP7B is expressed in the mammalian brain where it synthesizes, among others, 7α-hydroxypregnenolone. However, it governs spatial memory and learning rather than locomotor activity. Thus, although CYP7B and 7α-hydroxypregnenolone are present in the brain of vertebrates, there functions are different in mammals and non-mammals.

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.

Hyatt, M.W., Georoff, T.A., Nollens, H.H., Wells, R.L., Clauss, T.M., Ialeggio, D.M., Harms, C.A., and Wack, A.N. (2015). Voriconazole Toxicity in Multiple Penguin Species. J Zoo Wildl Med 46, 880-888.

Koyama, T., Haraguchi, S., Vaudry, H., and Tsutsui, K. (2009). Diurnal changes in the synthesis of the neurosteroid 7alpha-hydroxypregnenolone stimulating locomotor activity in newts. Ann N Y Acad Sci 1163, 444-447.

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.

Onuma, T.A., Ban, M., Makino, K., Katsumata, H., Hu, W., Ando, H., Fukuwaka, M.A., Azumaya, T., and Urano, A. (2010). Changes in gene expression for GH/PRL/SL family hormones in the pituitaries of homing chum salmon during ocean migration through upstream migration. Gen Comp Endocrinol 166, 537-548.

Tsutsui, K., Inoue, K., Miyabara, H., Suzuki, S., Ogura, Y., and Haraguchi, S. (2008). 7Alpha-hydroxypregnenolone mediates melatonin action underlying diurnal locomotor rhythms. J Neurosci 28, 2158-2167.