API

Aop: 195

AOP Title

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5-hydroxytryptamine transporter (5-HTT) inhibition leading to population increase

Short name:

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5-HTT leading to population increase

Authors

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Kellie Fay


Point of Contact Kellie Fay


Contributors

  • Kellie Fay

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on February 03, 2017 09:36

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Revision dates for related pages

Page Revision Date/Time
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) November 29, 2016 19:17
Increased, serotonin (5-HT) January 17, 2017 00:48
Increased, oocyte maturation January 17, 2017 00:55
Increased, Population December 03, 2016 16:37
induced spawning January 13, 2017 15:38
Increased, valve movement December 03, 2016 16:37
Increased, Reproductive Success December 03, 2016 16:37
Increase, cilia movement January 13, 2017 16:27
Increased, serotonin (5-HT) leads to Increased, oocyte maturation December 03, 2016 16:38
Increased, Reproductive Success leads to Increased, Population December 03, 2016 16:38
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, serotonin (5-HT) December 03, 2016 16:37
Increased, serotonin (5-HT) leads to Increased, valve movement January 17, 2017 01:02
Increased, oocyte maturation leads to induced spawning January 17, 2017 01:02
Increased, valve movement leads to induced spawning January 13, 2017 15:44
induced spawning leads to Increased, Reproductive Success January 13, 2017 16:47
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increase, cilia movement January 13, 2017 15:43
Increase, cilia movement leads to induced spawning January 13, 2017 15:45
Increased, serotonin (5-HT) leads to Increase, cilia movement January 30, 2017 12:20
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, oocyte maturation January 30, 2017 13:25
Fluoxetine November 29, 2016 18:42
Fluvoxamine November 29, 2016 18:42

Abstract

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Increased serotonergic activity resulting from the inhibition of the 5-hydroxytryptamin transporter (5-HTT; SERT; serotonin reuptake transporter) may result in increased population levels of certain mollusks, specifically invasive mussels. Gamete maturation and release are under serotonergic control and several mussel species have been reported to release viable gametes (both sperm and oocytes)upon exposure to serotonin or 5-HTT inhibitors, which increase serotonergic signalling. Given the critically low population levels of many Unionid species and the difficulty in managing several invasive (Dreissenid; e.g., zebra mussel) species, increased reproductive success of these invasive species may result in adverse outcomes at an ecosystem level.


Background (optional)

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This AOP was developed, initially, as a case study in developing an AOP for species with known or suscpected chemical exposures, in "Practical approaches to adverse outcome pathway (AOP) development and weight of evidence evaluation as illustrated by ecotoxicological case studies" by Fay et al. 2017.


Summary of the AOP

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Stressors

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Name Evidence
Fluoxetine
Fluvoxamine

Molecular Initiating Event

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Title Short name
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT)

Key Events

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Title Short name
Increased, serotonin (5-HT) Increased, serotonin (5-HT)
Increased, oocyte maturation Increased, oocyte maturation
induced spawning induced spawning
Increased, valve movement Increased, valve movement
Increased, Reproductive Success Increased, Reproductive Success
Increase, cilia movement Increase, cilia movement

Adverse Outcome

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Title Short name
Increased, Population Increased, Population

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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Is the AOP specific to certain tissues, life stages / age classes? Indicate if there are critical life stages, where exposure must occur, to results in the final adverse effect. Or specify if there are key events along the pathway which are dependent on the life stage although the AOP is known to be initiated regardless of life stage. Indicate also if the AOP is associated also with age- or sex-dependence. Instructions To add a life stage term to an AOP page, under “Life Stage Applicability” select ‘add life stage term.’ User will be directed to a page entitled “Add Life Stage to AOP.” This page will list the AOP name, with drop down menu options to select a Life Stage term and Evidence. Evidence can be left blank and added later. To edit a life stage term on an AOP page, under “Life Stage Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Life Stage” where they can edit the Evidence field using the drop down menu. Clicking ‘Update Aop life stage’ will update the Evidence field and redirect the user back to the AOP page.

Taxonomic Applicability

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Term Scientific Term Evidence Link
Argopecten irradians Argopecten irradians Weak NCBI
Mercenaria mercenaria Mercenaria mercenaria Weak NCBI
Arctica islandica Arctica islandica Weak NCBI
Spisula solidissima Spisula solidissima Weak NCBI
Anodonta cygnea Anodonta cygnea Weak NCBI
Dreissena polymorpha Dreissena polymorpha Weak NCBI

Sex Applicability

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Indicate the relevant domain of applicability with respect to sex. Instructions To add a taxonomic term to an AOP page, under “Taxonomic Applicability” select ‘add taxonomic term.’ User will be directed to a page entitled “Adding Taxonomic Term to AOP.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later. To edit a taxonomic term on an AOP page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the AOP page.

Graphical Representation

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Click to download graphical representation template

An additional form of data summation is the flow diagram of the intermediate events associated with the AOP. This graphical version of the AOP shows visually the sequence of events at the different levels of biological organisation.
 
 Instructions
 
 If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Browse…’ under the “Graphical Representation” heading, which is part of the "Summary of the AOP" section, to select the file that you have just edited. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading.
 
 If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Once the diagram is edited to its final state, upload the image file as described above.

Overall Assessment of the AOP

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This aop should be considered highly putative. SSRI effects in mussels have been fairly well documented as a method to increase reproduction in aquaculture settings, but the implications on natural population and potential ecosystem effects are unknown.

Domain of Applicability

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Bivalve populations which employ a broadcast spawning strategy for reproduction appear to be susceptible, including several 'invasive' species: zebra mussels, dark false mussels, and mediterranean mussels.  Several species of clams and scallops also release viable gametes upon exposure to serotonin reuptake inhibitors or serotonin.

 


Essentiality of the Key Events

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1). Instructions To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Essentiality of the Key Events” section on the AOP page.

Weight of Evidence Summary

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Biological plausibility:  Biological plausibility refers to the structural or funtional relationships between the key events based on our understanding of  'normal biology'. Nerves immunoreactive to serotonin have been identified in the CNS and gonads of scallops and clams (e.g., Natsutani and Nomura, 1986; Masseau et al., 2002; Siniscalchi et al., 2004).  Serotonin-reactive sites are also present on the surfaces of bivalve oocytes and serotonin controls germinal vesicle breakdown and, in at least some species, the progression from prophase to metaphase I (Hirai et al., 1994; Fong et al., 1994; Alvarado-Alvarez et al.,1996).  Thus, the link between antagonising the serotonin reuptake transporter, which results in longer residence time of serotonin in synaptic junctions and increased serotonerigic signalling, and increased spawning and reproductive success is highly plausible.

Dose-response concordance:  While there are abundant studies in many species of bivalves indicating exposure to various serotonin reuptake inhibitors or to serotonin results in spawning in both males and females, there are not many direct comparisons available of the concentrations required to trigger upstream events vs concentrations required to trigger downstream events.

 


Quantitative Considerations

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Exposure effects are not only concentration-dependent, but also season-dependent (see Ram et al., 1993).  Spawning in males appears to be more sensitive to increased serotonin than in females, at least in fingernail clams, surf clams, dark false mussels and zebra mussles (see table and references).


Considerations for Potential Applications of the AOP (optional)

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The reproductive sensitivity of many bivalves has been well-sutdied.  For commercially-important species, some aquaculture facilities employ fluoxetine or other SSRIs to promote reproduction.  Potential future applications of this AOP may involve pharmacological control of invasive species.


References

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List the bibliographic references to original papers, books or other documents used to support the AOP. Instructions To edit the “References” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “References” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “References” section on the AOP page.