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Relationship: 3474

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

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

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

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

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, extracellular serotonin

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding	adjacent	High	Not Specified	John Frisch (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
fish	fish	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

5-hydroxytryptamine transporter (5-HTT; SERT) is responsible for transporting serotonin through presynaptic receptors into nerve cells (Correia et al. 2023). When 5-hydroxytryptamine transporter activity is inhibited, serotonin reuptake is diminished, resulting in increased extracellular serotonin levels.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship 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. McDonald (2017) focused on using an Adverse Outcome Pathway 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.

Cited empirical studies are focused on inhibition of 5-hydroxytryptamine transporter and resulting increased extracellular serotonin levels in fish, in support of development of AOP 568 for McDonald (2017) content.

Authors of KER 3474 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Inhibition of 5-hydroxytryptamine transporter and resulting increased extracellular levels of serotonin has been studied in a limited number of fish systems, primarily in the laboratory of McDonald. It can be difficult and expensive to measure small extracellular concentrations of serotonin, and measurements of serotonin and the metabolite 5-hydroxyindoleactetic acid in tissue allows for the introduction of metabolism as possible influence on serotonin concentrations in addition to inhibition of transport by 5-hydroxytryptamine transporter (McDonald 2017). There has been more extensive study in laboratory mammals (see Ramsteijn et al. 2020 for review). In fish, SSRI injection studies have shown a consistent response in inhibition of 5-hydroxytryptamine transporter leading to increased extracellular levels of serotonin. Empirical mammal studies show additional support for the mechanism of inhibition of 5-hydroxytryptamine transporter leading to increased extracellular levels of serotonin because of the evolutionarily and functionally conserved pathways modulated by the neurotransmitter serotonin.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Species	Duration	Dose	Decreased 5-HTT; SERT activity?	Increased extracellular serotonin?	Summary	Citation
Gulf toadfish (Opsanus beta)	1 day	25 and 50 ug/g fluoxetine by intraperitoneal injection.	yes	yes	Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at both 25 and 50 ug/g doses tested.	Morando et al. (2009)
Gulf toadfish (Opsanus beta)	1 day	10 and 25 ug/g fluoxetine by intraperitoneal injection.	yes	yes	Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at both 10 and 25 ug/g doses tested.	McDonald et al. (2011)
Gulf toadfish (Opsanus beta)	1 day	1, 10 and 50 ug/g fluoxetine by intraperitoneal injection.	yes	yes	Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at 10 and 50 ug/g between 15-120 minutes.	Amador and McDonald (2018)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. 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.

References

List of the literature that was cited for this KER description. More help

Amador, M.H.B. and McDonald, M.D. 2018. Molecular and functional characterization of the Gulf toadfish serotonin transporter SLC6A4. Journal of Experimental Biology 221: jeb170928.

Correia, D., Domingues, I., Faria, M., and Oliveira, M. 2023. Effects of fluoxetine on fish: What do we know and where should we focus our efforts in the future? Science of the Total Environment 857: 159486.

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. McDonald,M.D., Gonzalez, A., and Sloman, K.A. 2011. Higher levels of aggression are observed in socially dominant toadfish treated with the selective serotonin reuptake inhibitor, fluoxetine. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 153: 107–112. Morando, M.B., Medeiros, L.R., and McDonald, M.D. 2009. Fluoxetine treatment affects nitrogen waste excretion and osmoregulation in a marine teleost fish. Aquatic Toxicology 95: 164–171.

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.

NOTE: Italics indicate edits from John Frisch January 2025.