API

Aop: 219

AOP Title

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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

Authors

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Florence Pagé-Larivière

Laval University, Quebec, Qc, Canada

florence.page-lariviere.1@ulaval.ca

Point of Contact

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Florence Pagé-Larivière

Contributors

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  • Florence Pagé-Larivière

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on June 26, 2017 21:02

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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
Decreased, Population trajectory April 18, 2017 16:19
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
Decreased, Reproductive Success leads to Decreased, Population trajectory May 09, 2017 10:02
Dopamine release in the brain, decreased leads to Sexual behavior, decreased May 09, 2017 10:06
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. 


Background (optional)

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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. 


Summary of the AOP

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Stressors

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Name Evidence Term
Ketoconazole

Molecular Initiating Event

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Title Short name
CYP7B activity, inhibition CYP7B activity, inhibition

Key Events

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Title Short name
7α-hydroxypregnenolone synthesis in the brain, decreased 7α-hydroxypregnenolone synthesis in the brain, decreased
Dopamine release in the brain, decreased Dopamine release in the brain, decreased
Sexual behavior, decreased Sexual behavior, decreased
Decreased, Reproductive Success Decreased, Reproductive Success

Adverse Outcome

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Title Short name
Decreased, Population trajectory Decreased, Population trajectory

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Adult, reproductively mature

Taxonomic Applicability

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Term Scientific Term Evidence Link
Japanese quail Coturnix japonica NCBI
Cynops pyrrhogaster Cynops pyrrhogaster NCBI

Sex Applicability

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Sex Evidence
Male

Graphical Representation

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Click to download graphical representation template

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Overall Assessment of the AOP

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Domain of Applicability

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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

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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.  


Weight of Evidence Summary

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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.


Quantitative Considerations

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This information is not available for the moment. 


Considerations for Potential Applications of the AOP (optional)

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References

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