API

Aop: 97

AOP Title

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5-hydroxytryptamine transporter (5-HTT; SERT) inhibition leading to population decline

Short name:

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5-HTT block to population decline

Authors

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Kellie Fay

Point of Contact

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Kellie Fay

Contributors

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  • 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 Do not cite Under Development 1.29 Included in OECD Work Plan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 January 13, 2017 10:53

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Revision dates for related pages

Page Revision Date/Time
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) September 16, 2017 10:15
Increase, predation December 03, 2016 16:37
Increased, muscular waves in foot September 16, 2017 10:15
Increased, water retention in foot December 03, 2016 16:37
Decline, Population December 03, 2016 16:33
Increased, valve movement December 03, 2016 16:37
Depletion, energy reserves December 03, 2016 16:37
Increased, foot detachment December 03, 2016 16:37
Increased, locomotion December 03, 2016 16:37
Increased, serotonin (5-HT) September 16, 2017 10:15
Depletion, energy reserves leads to Increase, predation December 03, 2016 16:38
Increased, locomotion leads to Increase, predation December 03, 2016 16:37
Increased, water retention in foot leads to Increased, valve movement December 03, 2016 16:38
Increased, valve movement leads to Increase, predation December 03, 2016 16:38
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, muscular waves in foot January 13, 2017 11:17
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, valve movement January 13, 2017 11:18
Increased, valve movement leads to Increased, water retention in foot December 03, 2016 16:38
Increased, muscular waves in foot leads to Increased, foot detachment December 03, 2016 16:37
Increased, water retention in foot leads to Increased, foot detachment December 03, 2016 16:38
Increased, muscular waves in foot leads to Increased, locomotion December 03, 2016 16:37
Increased, valve movement leads to Depletion, energy reserves December 03, 2016 16:38
Increased, locomotion leads to Depletion, energy reserves December 03, 2016 16:38
Increase, predation leads to Decline, Population December 03, 2016 16:38
Increased, foot detachment leads to Depletion, energy reserves December 03, 2016 16:38
Increased, serotonin (5-HT) leads to Increased, valve movement January 17, 2017 01:02
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, muscular waves in foot January 30, 2017 11:17
Fluoxetine November 29, 2016 18:42

Abstract

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Anti-depressants such as fluoxetine and sertraline inhibit the reuptake of 5-hydroxytryptamine (5-HT; serotonin)  by blocking the 5-HT transporter (5-HTT), causing an increase in serotonin levels at neural junctions. In molluscs, serotonergic neurons are responsible for the termination of the catch state of muscle contraction (Muneoka and Twarog, 1983). During catch, muscles contract and are resistant to stretch well after excitation by acetylcholine has stopped and intracellular Ca2+ stores return to normal. Importantly, this prolonged contraction is accomplished with minimal (or no) use of energy. While additional phyla may also be able to undergo catch contraction, the role of serotonin in releasing the contraction state appears to be unique to mollusks (Muneoka and Twarog, 1983). In bivalves, catch is used to maintain valve (shell) closure and the presence of serotonin promotes the transition from the passive state to active valve movement; exposure to 5-HTT inhibitors has been observed to cause increased valve movement in swan mussels (Cunha and Machado, 2001). Increased valve movement not only depletes the organism’s energy reserves,but can cause excess water retention in the foot. This water retention is speculated to cause the foot detachment observed in mussels exposed to 5-HTT inhibitors (Cunha and Machado, 2001), although terrestrial gastropods also experience foot detachement (Pavlova 2001). Mussels in the unattached state expend greater energy [54] and are more susceptibility to predation than those attached to a substrate and clumped together (Casey and Chattopadhyay, 2008).

Serotonin has also been identified as a primary neurotransmitter used to control both ciliary and pedal foot locomotion in land and aquatic mollusks (Muneoka et al 1983, Pavlova 2001 , Gosselin 1961, Longley 2010). The specific impacts on locomotion, as well as the concentration-dependence, varies among molluscs because of differing physiology and life history strategies (Fong, 2014). In various bivalves, movement alterations may take the form of increased valve movement, locomotion and mantle display, and/or increased burrowing or burrowing (inappropriately) during daylight hours. The untimely and excessive movement of molluscs due to amplified serotonergic activity could feasibly enhance their visibility and/or diminish their energy reserves, making them more susceptible to predation. Recently, prolonged, low-dose (30-300 ng/L) exposures of mussels to fluoxetine were reported to cause decreases in filter feeding rates, energy reserves and growth (Peters 2016). Foot detachment mentioned above has also been attributed to disrupted coordination of pedal muscle cells and ciliated epithelium of the foot (Pavlova 2001).

 


Background (optional)

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Summary of the AOP

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Stressors

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Name Evidence Term
Fluoxetine

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, muscular waves in foot Increased, muscular waves in foot
Increased, water retention in foot Increased, water retention in foot
Increased, valve movement Increased, valve movement
Depletion, energy reserves Depletion, energy reserves
Increased, foot detachment Increased, foot detachment
Increased, locomotion Increased, locomotion
Increased, serotonin (5-HT) Increased, serotonin (5-HT)

Adverse Outcome

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Title Short name
Increase, predation Increase, predation
Decline, Population Decline, Population

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Depletion, energy reserves leads to Increase, predation Directly leads to
Increased, locomotion leads to Increase, predation Directly leads to
Increased, water retention in foot leads to Increased, valve movement Directly leads to Moderate
Increased, valve movement leads to Increase, predation Directly leads to
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, muscular waves in foot Indirectly leads to
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, valve movement Indirectly leads to
Increased, valve movement leads to Increased, water retention in foot Directly leads to
Increased, muscular waves in foot leads to Increased, foot detachment Directly leads to
Increased, water retention in foot leads to Increased, foot detachment Directly leads to
Increased, muscular waves in foot leads to Increased, locomotion Directly leads to
Increased, valve movement leads to Depletion, energy reserves Directly leads to
Increased, locomotion leads to Depletion, energy reserves Directly leads to
Increase, predation leads to Decline, Population Directly leads to
Increased, foot detachment leads to Depletion, energy reserves Directly leads to
Increased, serotonin (5-HT) leads to Increased, valve movement Directly leads to
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, serotonin (5-HT) Directly leads to
Increased, serotonin (5-HT) leads to Increased, muscular waves in foot Directly leads to

Network View

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Life Stage Applicability

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Life stage Evidence
Juvenile Moderate
Adult Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Mytilus galloprovincialis Mytilus galloprovincialis NCBI
tritonea diomedea tritonea diomedea NCBI
Lymnaea stagnalis Lymnaea stagnalis NCBI
Melibe leonine Melibe leonine NCBI
Helix lucorum Helix lucorum NCBI
Lampsilis fasciola Lampsilis fasciola NCBI

Sex Applicability

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Sex Evidence
Male
Female
Hermaphrodite

Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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This putative AOP should be considered preliminary only.

Domain of Applicability

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Life Stage Applicability Movement-related and energy depletion are also specific to juvenile and adult mussels. Taxonomic Applicability To relate the MIE for aquatic species, an assessment of the conservation of this target across taxa was a primary step in establishing biological plausibility. Because pharmaceuticals present in aquatic environments have known activity to human targets, the human 5-HTT was used as the query protein in a SeqAPASS analysis. The results indicated substantial conservation across a broad spectrum of major animal classes for which there were data. Within the scope of potentially exposed aquatic taxa (fish, turtles, crustaceans, bivalves, etc), the high degree of conservation at the levels of the primary amino acid sequence and functional domain (solute-binding domain) suggests exposure to drugs which interact with the human transporter would likewise inhibit orthologous transporters in these taxa. Within the phylum molluska, this aop was developed with specific focus on bivalves although several key events are likely applicable to other taxa. Some key events may be unique to specific bivalve taxa due to different life history strategies.  An attempt to distinguish between relevant taxa for each key event has been made within each event page. Sex Applicability

 


Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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