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AOP: 568

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

Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Of the originating work: M. Danielle McDonald, University of Miami, Florida.

Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division.  

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
John Frisch   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • John Frisch

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on January 30, 2025 11:40

Revision dates for related pages

Page Revision Date/Time
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) January 14, 2025 09:48
Increased, extracellular serotonin January 14, 2025 09:52
Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors January 14, 2025 10:23
Inhibition, Feeding January 14, 2025 10:26
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, extracellular serotonin January 14, 2025 09:28
Increased, extracellular serotonin leads to Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors January 14, 2025 09:37
Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors leads to Inhibition, Feeding January 14, 2025 09:43
SSRI (Selective serotonin reuptake inhibitor) April 13, 2017 15:32

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

Serotonin reuptake transporter (SERT; 5-hydroxytryptamine transporter; 5-HTT) is a member of the neurotransmitter sodium symporter (NSS) family that includes the dopamine (DAT), norepinephrine (NET), and Gamma-aminobutyric acid (GABA) transporters (Yang and Gouaux 2021).  SERT transports the neurotransmitter serotonin from the synaptic cleft back into presynaptic neurons, a process commonly referred to as reuptake.  SERT binds to sodium, then serotonin, then chloride in order to allow transport of serotonin into the neuron, and binding to potassium allows SERT to be released by the cell in outward configuration available for transport of serotonin (Yang and Gouaux 2021).  Selective serotonin reuptake inhibitor (SSRI) antidepressants are a class of compounds known to inhibit serotonin reuptake transporter activity resulting in increased extracellular serotonin levels, and enter the aquatic environment when not removed by wastewater treatment (McDonald 2017).

Serotonin (5-HT) is a neurotransmitter which stimulates pathways resulting in a variety of downstream behavior effects including increased stress, increased anxiety, decreased aggression, decreased appetite, increased lethargy, decreased locomotion, learning inhibition, and decreased reproduction (McDonald 2017; Ramsteijn et al. 2020).  Activation of different pathways is modulated by different receptors located in different tissue types, with serotonin receptors classified into 7 families and 14 receptor subtypes (McDonald 2017; Barnes et al. 2021).   

Inhibition of feeding can be caused by appetite suppression from brain signals, a reduced ability to capture prey, increased lethargy, and reduction in locomotion activity.  Increased stimulation of brain serotonin 5-HT1a, 5-HT2c receptors is one mechanism that has been shown to decrease feeding by appetite suppression, in empirical studies that used agonist compounds that block specific serotonin receptors (Ortega et al. 2013; Perez-Maceira et al. 2014; Perez-Maceria et al. 2016; Barnes et al. 2021).

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

This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages. 

The focus of the originating work was to use an AOP framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals.    

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

The originating authors used an AOP framework to develop pathways related to SSRI exposure in fish, and Read-Across hypothesis to link empirical studies in laboratory mammals to functionally conserved effects in fish.

The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.    

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

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 1320 Increased, extracellular serotonin Increased, extracellular serotonin
KE 2308 Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors
AO 1016 Inhibition, Feeding Inhibition, Feeding

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

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

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages 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
fish fish High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

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

1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?

Key Event Relationship (KER)

Level of Support  

Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance.

Moderate = Support of the relationship based on limited empirical studies, with some uncertainty of the exclusivity of the receptors involved, and acknowledgement of the involvement of additional signaling molecules.

Relationship 3474: Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, extracellular serotonin

Strong support.  The relationship between inhibition of 5-hydroxytryptamine transporter (5-HTT; SERT) and increased extracellular serotonin is broadly accepted and supported among fish, laboratory mammal, and fish data.

Relationship 3475: Increased, extracellular serotonin leads to Increased, stimulation of brain 5-HT1a, 5-HT2c receptors

Strong support.  The relationship between increased extracellular serotonin and increased stimulation of brain 5-HT1a, 5-HT2c receptors is broadly accepted and supported among fish, laboratory mammal, and fish data.

Relationship 3476: Increased, stimulation of brain 5-HT1a, 5-HT2c receptors leads to Inhibition, feeding

Moderate support. The relationship between increased stimulation of brain 5-HT1a, 5-HT2c receptors and inhibition of feeding is consistent with established empirical studies.  The number of studies that link inhibition of feeding to brain 5-HT1a, 5-HT2c receptors is limited, with the stimulation of other serotonin receptors a possible influence on feeding response.  In addition, activation of serotonin-induced pathways stimulates production of appetite-regulating neuropeptides, with the observed behavioral effect of reduced feeding.

Overall

Moderate to strong support.  Extensive understanding of the relationships between events from empirical studies from fish, laboratory mammals, and humans.   More limited support for the exclusivity of brain 5-HT1a, 5-HT2c receptors in inducing inhibition of feeding, and an acknowledgment of the involvement of additional signaling molecules.

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: Applies to all life stages with developed brain and central nervous systems.

Sex: Applies to both males and females.

Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.  

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

2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Key Event (KE)

Level of Support

Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events.

Moderate = Some evidence from experimental studies supporting the relationship, with additional internal and external environmental factors impacting the relationship.

KE 619 Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT)

Strong support.  Inhibition of 5-hydroxytryptamine transporter (SERT) leads to increased extracellular serotonin.  Evidence is available from studies of radiolabeled compounds, enzyme immunoassay, and toxicant studies measuring enzyme activity, protein levels, and movement of serotonin into nerve cells.  Best evidence for the essentiality of activation of 5-hydroxytryptamine transporter is through toxicant studies of selective serotonin reuptake inhibitors (SSRIs) that inhibit 5-hydroxytryptamine transporter activity and lead to increased levels of extracellular serotonin, with normal 5-hydroxytryptamine transporter activity in the absence of the SSRI compound.  The mechanism in which SERT binds to sodium, then serotonin, then chloride in order to allow transport of serotonin into neurons has been established.

KE 1320 Increased, extracellular serotonin

Strong support.  Increased extracellular serotonin (5-HT) leads to increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Evidence is available from serotonin addition, enzyme immunoassay, and toxicant studies measuring enzyme activity and protein levels.  Families and subclasses of receptors that are stimulated by serotonin have been well-established.  Best evidence for the essentiality of increased stimulation specific to brain 5-HT1a and 5-HT2c receptors is in the use of agonist compounds known to block a specific serotonin receptor, and contrasting to treatment without the agonist agent.  In some cases the relationship between increased levels of serotonin and increased simulation of serotonin receptors is assumed and study focus placed on downstream effects of activation of serotonin pathways and/or behavior effects.

KE 2308 Increased, stimulation of brain 5-HT1a, 5-HT2c receptors

Moderate support.  Increased stimulation of brain 5-HT1a and 5-HT2c receptors leads to inhibition of feeding.  Evidence is available from serotonin addition, enzyme immunoassay, toxicant, and behavior studies.   Best evidence for essentiality of simulation of brain 5-HT1a and 5-HT2c receptors is in the use of agonist compounds known to block a specific serotonin receptor and observed inhibition of feeding by rate of food intake, and contrasting to treatment without the agonist agent where normal feeding is maintained.  Empirical evidence has the caveat that additional signaling molecules are involved in modulating feeding response, and that feeding rate is influenced by both internal and external environmental factors.

KE 1016 Inhibition, feeding

This is the final event of the AOP.

Overall

Moderate to strong support.  Direct evidence from empirical studies from fish, laboratory mammals, and humans for all key events.   Moderate support for the relationship between simulation of brain 5-HT1a, 5-HT2c receptors and inhibition of feeding because of the influence of additional internal and external environmental factors.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

3. Empirical Support for Key Event Relationship: Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown?

Key Event Relationship (KER)

Level of Support 

Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions. 

Relationship 3474: Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, extracellular serotonin

Strong support.  Inhibition of 5-hydroxytryptamine transporter (SERT) leads to increased extracellular serotonin.  Evidence is available from studies of radiolabeled compounds, enzyme immunoassay, and toxicant studies measuring enzyme activity, protein levels, and movement of serotonin into nerve cells.  Inhibition of 5-hydroxytryptamine transporter (SERT) occurred earlier in the time-course of exposure than increased extracellular serotonin, and the concentrations that inhibited 5-hydroxytryptamine transporter were equal to or lower than the concentrations that increased extracellular serotonin.   Therefore, the data support a causal relationship.

Relationship 3475: Increased, extracellular serotonin leads to Increased, stimulation of brain 5-HT1a, 5-HT2c receptors

Strong support. Increased extracellular serotonin (5-HT) leads to increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Evidence is available from serotonin addition, enzyme immunoassay, and toxicant studies measuring enzyme activity and protein levels.  Increased extracellular serotonin occurred earlier in the time-course of exposure than increased stimulation of brain 5-HT1a and 5-HT2c receptors, and the concentrations that increased extracellular serotonin were equal to or lower than the concentrations that increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Therefore, the data support a causal relationship.

Relationship 3476: Increased, stimulation of brain 5-HT1a, 5-HT2c receptors leads to Inhibition, feeding

Strong support. Increased stimulation of brain 5-HT1a and 5-HT2c receptors leads to inhibition of feeding.  Evidence is available from serotonin addition, enzyme immunoassay, toxicant, and behavior studies.  Increased stimulation of brain 5-HT1a and 5-HT2c receptors occurred earlier in the time-course of exposure than inhibition of feeding, and the concentrations that increased stimulation of brain 5-HT1a and 5-HT2c receptors were equal to or lower than the concentrations that inhibited feeding.  Therefore, the data support a causal relationship.

Overall

Strong support.  Evidence from empirical studies shows consistent change in both events including frequent testing in fish and lab mammals, with upstream events occurring earlier in the time-course of exposure and at equal or lower concentrations than downstream events, supporting causal relationships.

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
Modulating Factor (MF) Influence or Outcome KER(s) involved
Selective Serotonin Reuptake Inhibitor (SSRI) Inhibits reuptake of serotonin by nerve cells by blocking receptors, increases extracellular serotonin. 3474

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

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

Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., Chaumont-Dubel, S., Claeysen, S., Cunningham, K.A., Fone, K.C., Gershon, M., Di Giovanni, G., Goodfellow, N.M., Halberstadt, A.L., Hartley, R.M., Hassaine, G., Herrick-Davis, K., Hovius, R., Lacivita, E., Lambe, E..K, Leopoldo, M., Levy, F.O., Lummis, S.C.R, Marin, P., Maroteaux, L., McCreary, A.C., Nelson, D.L., Neumaier, J.F., Newman-Tancredi, A., Nury, H., Roberts, A., Roth, B.L., Roumier, A., Sanger, G.J., Teitler, M., Sharp, T., Villalon, C.M., Vogel, H., Watts, S.W., and  Hoyer, D. 2021.  International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacological Reviews 73(1): 310-520.

McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31.

Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196.

Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6.

Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321.

Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69.

Rand-Weaver, M., Margiotta-Casaluci, L., Patel, A., Panter, G.H., Owen, S.F., and Sumpter, J.P.  2013. The read-across hypothesis and environmental risk assessment of pharmaceuticals. Environmental Science Technology 47: 11384–11395.

Yang, D. and Gouaux, E. 2021.  Illumination of serotonin transporter mechanism and role of the allosteric site. Science Advances 7(49): eabl3857.