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AOP: 219

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior

Short name
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Inhibition of CYP7B activity leads to decreased sexual behavior
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Handbook Version v1.0

Graphical Representation

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Authors

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Florence Pagé-Larivière

Laval University, Quebec, Qc, Canada

florence.page-lariviere.1@ulaval.ca

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

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  • Florence Pagé-Larivière
  • Arthur Author

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
CYP7B activity, inhibition May 17, 2017 12:21
7α-hydroxypregnenolone synthesis in the brain, decreased May 17, 2017 13:08
Dopamine release in the brain, decreased May 17, 2017 13:05
Sexual behavior, decreased May 17, 2017 21:17
Decreased, Reproductive Success December 03, 2016 16:37
Decrease, Population growth rate January 03, 2023 09:09
CYP7B activity, inhibition leads to 7α-hydroxypregnenolone synthesis in the brain, decreased May 17, 2017 21:09
7α-hydroxypregnenolone synthesis in the brain, decreased leads to Sexual behavior, decreased May 17, 2017 22:00
7α-hydroxypregnenolone synthesis in the brain, decreased leads to Dopamine release in the brain, decreased May 25, 2017 14:22
Sexual behavior, decreased leads to Decreased, Reproductive Success May 08, 2017 11:20
Dopamine release in the brain, decreased leads to Sexual behavior, decreased May 09, 2017 10:06
Decreased, Reproductive Success leads to Decrease, Population growth rate April 06, 2022 13:50
Ketoconazole May 02, 2017 11:08

Abstract

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This AOP details the linkage between CYP7B inhibition and decreased sexual behavior that adversely impacts reproductive success. CYP7B is expressed in the brain and catalyzes the conversion of pregnenolone to 7α-hydroxypregnenolone, a neurosteroid that stimulates the release of dopamine in the telencephalon. When released through this pathway, dopamine binds D2 receptor which is involved in induction of sexual behaviors, among other effects. Ketoconazole and other azole fungicides are potent inhibitor of cytochrome P450s, including CYP7B. They bind to the heme site of the enzyme preventing its catalytic activity. When exposed to one of these molecules, 7α-hydroxypregnenolone synthesis decreases which, in turn, reduces dopamine release in the telencephalon and limits sexual behavior. Since sexual behaviors are closely associated to reproductive success, its inhibition negatively affects the fitness of animals. 

7α-hydroxypregnenolone was recently discovered and its function and regulation remain unclear. The few studies that focused on this neurosteroid and that were used for this AOP are based on in vitro and in vivo experiments quail and newt. Since the function of this neurosteroid differs in mammals, this AOP is only applicable to non-mammalian vertebrates. It is also limited to male. 

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This AOP shares most of its key events with AOP 218, with the exception of Locomotor activity, decreased (Event 1389). Due to this difference, the domain of applicability of the two AOPs differs and limits their compatibility. For that reason, two similar AOPs with different domain of applicability were created. 

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1386 CYP7B activity, inhibition CYP7B activity, inhibition
KE 1387 7α-hydroxypregnenolone synthesis in the brain, decreased 7α-hydroxypregnenolone synthesis in the brain, decreased
KE 1388 Dopamine release in the brain, decreased Dopamine release in the brain, decreased
KE 1390 Sexual behavior, decreased Sexual behavior, decreased
KE 1141 Decreased, Reproductive Success Decreased, Reproductive Success
AO 360 Decrease, Population growth rate Decrease, Population growth rate

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
CYP7B activity, inhibition leads to 7α-hydroxypregnenolone synthesis in the brain, decreased adjacent
7α-hydroxypregnenolone synthesis in the brain, decreased leads to Dopamine release in the brain, decreased adjacent
Sexual behavior, decreased leads to Decreased, Reproductive Success adjacent
Dopamine release in the brain, decreased leads to Sexual behavior, decreased adjacent
Decreased, Reproductive Success leads to Decrease, Population growth rate adjacent
7α-hydroxypregnenolone synthesis in the brain, decreased leads to Sexual behavior, decreased non-adjacent

Network View

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Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help
Name
Ketoconazole

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult, reproductively mature

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Japanese quail Coturnix japonica NCBI
Cynops pyrrhogaster Cynops pyrrhogaster NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Taxons: This AOP is supported with evidence from studies conducted with newt and quail. Based on anticipated conservation of the biology associated with the KEs and KERs described, it is presumed to be applicable to all amphibian and bird. 

Previous evidence suggest that this AOP is not applicable to mammal. All the key events of this AOP are described or are biologically plausible in mammal, but the relationship between them might differ, as suggested by Yau et al. (2006). 

Sex: This AOP is applicable to male only. 

Life Stage: This AOP applies to sexually mature animals since the endpoint is related to reproduction. 

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Few studies measured multiple key events of this AOP.  For this reason, the evidence for essentiality of the key events is mainly indirect and provided by a series of antagonist/exogenous supplementation experiments. The animal models used for these investigations were newt and quail. 

Key event

Essentiality

Rational

MIE

Inhibition of CYP7B

Moderate

At present, no CYP7B knock-out experiments were conducted in species of interest. However, several indirect evidences linking CYP7B inhibition to a decreased locomotor activity suggest an important correlation between the two events.

  • Inhibition of CYP7B with intracranial injection of ketoconazole decreased 7α-hydroxypregnenolone synthesis and decreased sexual behavior in newt and quail (Ogura et al., 2016, Toyoda et al., 2012). Ketoconazole is a non-specific inhibitor of cytochromes P450 activity known to bind to and inhibit CYP7B both in vitro and in vivo.

KE1

7α-hydroxypregnenolone, decreased

Strong

Direct evidences connecting this neurosteroid to sexual behavior were described.

  • Intracerebroventricular injection of 7α-hydroxypregnenolone in male quail and newt induced spontaneous sexual behavior in a dose-dependent manner. The same treatment had no effect on female (Toyoda et al., 2012; Ogura et al., 2016).

KE2

Dopamine release, decreased

Moderate

There is strong evidence demonstrating the involvement of dopamine in sexual behavior among all vertebrates. However, only indirect evidence relates CYP7B inhibition to a decreased dopamine release. The rational is stronger for 7α-hydroxypregnenolone in relation to dopamine release, although this neurosteroid receptor remains to be identified. 

  • Sexual behavior was stimulated in male newt with intracerebroventricular injection of 7α-hydroxypregnenolone. Newt treated with a dopamine D2-like receptor antagonist (haloperidol or sulpiride) prior to receiving 7α-hydroxypregnenolone exhibited no increase in sexual behavior (Toyoda et al., 2012).

KE3

Locomotor activity, decreased

Strong

All the previous key events can decrease sexual behavior in male quail and newt.  

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological plausibility

This AOP connects the CYP7B catalyzed synthesis on an important neurosteroid to a well characterized sequence of events. For instance, the involvement of dopamine in sexual behavior that in turn impacts on reproductive success is well described and undisputed (Melis et al., 1995; Hull et al., 2004). What is less characterized is the relation between 7α-hydroxypregnenolone and dopamine release. 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.

In terms of structural plausibility, the brain expresses the steroidogenic enzymes required for pregnenolone synthesis, the main substrate of CYP7B. It also expresses CYP7B which synthesizes high concentration of 7α-hydroxypregnenolone in the diencephalon. This region of the brain is populated by neurons projecting into the striatum which is known to express a high quantity of D1- and D2-like dopamine receptor and control motor activity (Orgen S. et al., 1986; Mezey S. et al., 2002; Callier S. et al., 2003).

Uncertainties or inconsistencie

At present, there are no inconsistencies reported in the literature, but some gaps remain to be filled.

The most important ones are 7α-hydroxypregnenolone receptor localization and the connection between 7α-hydroxypregnenolone and dopamine release discussed in the previous section.

In addition, mammalian CYP7B not only catalyzes the 7α-hydroxylation of pregnenolone but also that of dehydroepiandrosterone (DHEA). Although no clear information reported this enzymatic reaction in the bird, it is plausible that CYP7B catalyzes the hydroxylation of DHEA. Thus, the phenotypic effect of CYP7B inhibition in the brain cannot be uniquely attributed to a depletion in 7α-hydroxypregnenolone. Additionally, ketoconazole is known to inhibit a variety of CYPs, which suggest that animal exposed to it are likely to have several other enzymes inhibited. It is plausible that the impacts of ketoconazole are the result of multiple CYPs inhibition that all converge towards the same phenotype. These off target effects greatly limit the investigations on 7α-hydroxypregnenolone since its concentration cannot be specifically decreased.

If a CYP7B knock-out in the brain was to be performed in an animal species, 7α-hydroxyDHEA supplementation would be required to properly study 7α-hydroxypregnenolone function.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

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This information is not available for the moment. 

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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