Aop: 97

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

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

Short name
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5-HTT block to population decline

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Kellie Fay

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
Kellie Fay   (email point of contact)

Contributors

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  • Kellie Fay

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome 1.29 Under Development
This AOP was last modified on April 12, 2022 13:48

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
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
Decrease, Population growth rate July 08, 2022 07:40
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
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
Increase, predation leads to Decrease, Population growth rate April 06, 2022 13:41
Fluoxetine November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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).

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

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 619 Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT)
KE 625 Increased, muscular waves in foot Increased, muscular waves in foot
KE 1139 Increased, water retention in foot Increased, water retention in foot
KE 1142 Increased, valve movement Increased, valve movement
KE 1143 Depletion, energy reserves Depletion, energy reserves
KE 624 Increased, foot detachment Increased, foot detachment
KE 622 Increased, locomotion Increased, locomotion
KE 626 Increased, serotonin (5-HT) Increased, serotonin (5-HT)
AO 623 Increase, predation Increase, predation
AO 360 Decrease, Population growth rate Decrease, Population growth rate

Relationships Between Two Key Events (Including MIEs and AOs)

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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
Fluoxetine

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Juvenile Moderate
Adult Moderate

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
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

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

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

This putative AOP should be considered preliminary only.

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

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

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

Evidence Assessment

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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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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