Aop:97

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Status

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https://aopwiki.org/aops/97


AOP Title

5-hydroxytryptamine transporter (5-HTT; SERT) inhibition leading to population decline
Short name: 5-HTT block to population decline

Authors

Kellie Fay

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

Anti-depressants such as fluoxetine inhibit the reuptake of 5-HT by blocking the 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 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 bivalves, movement alterations may take the form of increased valve movement, locomotion and mantle display (in Dreissenids), 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).

While movement-related endpoints in molluscs may be highly sensitive to 5-HTT inhibition, empirical evidence also supports a putative AO for reproductive health because serotonin is reported to control oocyte maturation, spawning and glochidia release (Ram 1993, Bringolf 2010, Meechonkit 2010,Lazarra 2012). Exposure of native freshwater mussels to fluoxetine induced premature release of glochidia resulting in non-viable larvae (Bringolf 2010). One review of fluoxetine effects in aquatic species noted that concentrations observed to impact the reproductive endpoints of mussels can far exceed environmental exposure levels (Sumpter 2014), and this may be a limitation of several key events depicted in this AOP network. However, recent work to address this concern supports several relevant effects at ng/L concentrations (Peters 2016, Ford 2016).

Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
5-hydroxytryptamine transporter (5-HTT; SERT), Inhibition

Key Events

Event Support for Essentiality
serotonin (5-HT), Increased
cilia movement, Increase
locomotion, Increased
muscular waves in foot, Increased
water retention in foot, Increased
Sexual maturity, Delayed
valve movement, Increased
energy reserves, Depletion
Spawning , premature
mantel display, increased or inappropriate
water pumping, Increased
parturition, induced

Adverse Outcome

Adverse Outcome
predation, Increase
Reproductive Success, Decreased
Population, Decline

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
5-hydroxytryptamine transporter (5-HTT; SERT), Inhibition Directly Leads to serotonin (5-HT), Increased
serotonin (5-HT), Increased Directly Leads to cilia movement, Increase
serotonin (5-HT), Increased Directly Leads to muscular waves in foot, Increased
muscular waves in foot, Increased Directly Leads to locomotion, Increased
serotonin (5-HT), Increased Directly Leads to valve movement, Increased Strong
valve movement, Increased Directly Leads to energy reserves, Depletion
Reproductive Success, Decreased Directly Leads to Population, Decline
energy reserves, Depletion Indirectly Leads to Sexual maturity, Delayed
Sexual maturity, Delayed Directly Leads to Reproductive Success, Decreased
predation, Increase Directly Leads to Population, Decline
energy reserves, Depletion Indirectly Leads to predation, Increase
serotonin (5-HT), Increased Indirectly Leads to locomotion, Increased
serotonin (5-HT), Increased Directly Leads to mantel display, increased or inappropriate Moderate
locomotion, Increased Indirectly Leads to predation, Increase
valve movement, Increased Directly Leads to water pumping, Increased Strong
cilia movement, Increase Directly Leads to water pumping, Increased Weak
cilia movement, Increase Directly Leads to energy reserves, Depletion
mantel display, increased or inappropriate Directly Leads to energy reserves, Depletion
mantel display, increased or inappropriate Directly Leads to parturition, induced
parturition, induced Directly Leads to Reproductive Success, Decreased
Spawning , premature Directly Leads to Reproductive Success, Decreased
water retention in foot, Increased Directly Leads to valve movement, Increased Moderate
water pumping, Increased Directly Leads to water retention in foot, Increased
water pumping, Increased Directly Leads to Spawning , premature
water pumping, Increased Directly Leads to parturition, induced
valve movement, Increased Indirectly Leads to predation, Increase
muscular waves in foot, Increased Directly Leads to energy reserves, Depletion

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Life Stage Applicability

Life Stage Evidence Links
Juvenile Moderate
Adult Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
Mytilus galloprovincialis Mytilus galloprovincialis NCBI
tritonea diomedea
Lymnaea stagnalis Lymnaea stagnalis NCBI
Melibe leonine
Helix lucorum Helix lucorum NCBI
Lampsilis fasciola Lampsilis fasciola NCBI

Sex Applicability

Sex Evidence Links
Male
Female
Hermaphrodite

Graphical Representation

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Overall Assessment of the AOP

This putative AOP should be considered preliminary only.

Domain of Applicability

Life Stage Applicability Juvenile and adult mussels are impacted by components of this aop network. Successfull metamorphosis in wavy-rayed lamp mussel glochidia was increased with exposure to fluoxetine (Hazelton et al, 2014), but the same study observed premature release of glochidia resulting in decreased viability in adults exposed to fluoxetine. 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 (e.g, not all species rely on mantel display or release glochidia in the same manner). An attempt to distinguish between relevant taxa for each key event has been made within each event page. Sex Applicability Spawning and gametogenesis effects are sex-specific, but serotonin is reported to induce spawning in both male and female mussels.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References