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Relationship: 3287

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

Decreased Na/K ATPase activity leads to Decreased, sodium uptake in gills

Upstream event

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

Decreased Na/K ATPase activity

Downstream event

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

Decreased, sodium uptake in gills

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
Decreased Sodium/Potassium ATPase activity leads to Heart failure	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 Do not cite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
Juvenile	High
Adult	High

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

Gills are a major organ for uptake of ions from the surrounding water environment through specialized cells known as ionocytes, with ionocytes having an important role in ion balance and osmoregulation (Hwang et al. 2011). Freshwater organisms are hypertonic (higher ion concentration) compared to the aquatic environment, requiring active transport of sodium. Sodium potassium adenosine triphosphatase (Na+/K+ ATPase) is a membrane protein that enables sodium uptake and resulting ion regulation. Na+/K+ ATPase uses energy from adenosine triphosphate to move sodium across membranes against its electrochemical gradient. Decrease in sodium uptake can be caused by decrease in enzyme activity.

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. Brix et al. (2022) focused on identifying Adverse Outcome Pathways associated with chronic copper exposure in aquatic vertebrates through review of existing literature, and provided initial network analysis.

Cited empirical studies are focused on Na+/K+ ATPase activity and resulting sodium uptake in freshwater fish, in support of development of AOP 539 for Brix et al. (2022) content.

Authors of KER 3287 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

Sodium potassium adenosine triphosphatase (Na+/K+ ATPase) activity has been studied via electrophysical studies of the movement of ions across membranes. Consistently across freshwater fish taxa, Na+/K+ ATPase occurs as a transmembrane protein, with an understood mechanism of using energy from adenosine triphosphate to move sodium across membranes against its electrochemical gradient. Through toxicant and inhibitor studies, evidence shows that decreases in Na+/K+ ATPase activity result in decreased sodium uptake across gills.

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 Na/K ATPase activity?	Decreased sodium uptake in gills?	Summary	Citation
Tilapia (Oreochromis mossambicus)	6 days	50, 100, 200 ug/L copper.	yes	yes	Mature female tilapia in flux chambers showed dose-dependence to exposure, at 200 ug/L statistically significant decreased Na/K ATPase activity and resulting decreased sodium uptake at 200 ug/L.	Pelgrom et al. (1995)
Rainbow trout (Oncorhynchus mykiss)	72 hours	2, 10 ug/L silver nitrate.	yes	yes	Trout in flux chambers, at 2 ug/L 50% decreased Na/K ATPase activity from control and at 10 ug/L showed statistically significant decreased Na/K ATPase activity and resulting decreased sodium uptake at 2, 10 ug/L.	Morgan et al. (1997)
Mummichog (Fundulus heteroclitus)	24 hours	110 ug/L copper in freshwater and additional salinities.	yes	yes	Mummichog in freshwater in flux chambers showed statistically significant decreased Na/K ATPase activity and resulting decreased sodium uptake.	Blanchard and Grosell (2006)
Rainbow trout (Oncorhynchus mykiss)	24 hours	15, 35, 100 ug/L copper sulfate.	yes	yes	Juvenile trout in flux chambers showed dose-dependence to exposure, at 100 ug/L statistically significant decreased Na/K ATPase activity and resulting decreased sodium uptake at 100 ug/L.	Chowdhury et al. (2016)

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 gills (ex. juvenile and adult)

Sex: Applies to both males and females; not sex-specific.

Taxonomic: Freshwater true chordates, with evidence primarily from fish.

References

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

Blanchard, J. and Grosell, M. 2006. Copper toxicity across salinities from freshwater to seawater in the euryhaline fish Fundulus heteroclitus: Is copper an ionoregulatory toxicant in high salinities? Aquatic Toxicology 80: 131–139.

Brix, K.V., De Boeck, G., Baken, S., and Fort, D.J. 2022. Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians. Environmental Toxicology and Chemistry 41(12): 2911-2927.

Chowdhury, M.J., Girgis, M., and Wood, C.M. 2016. Revisiting the mechanisms of copper toxicity to rainbow trout: Timecourse, influence of calcium, unidirectional Na+ fluxes, and branchial Na+, K+ ATPase and V-type H+ ATPase activities. Aquatic Toxicology 177: 51–62.

Hwang, P.-P., Lee, T.-H., and Lin, L.-Y. 2011. Ion regulation in fish gills: recent progress in the cellular and molecular mechanisms. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 301: R28–R47.

Morgan, I.J., Henry, R.P., and Wood, C.M. 1997. The mechanism of acute silver nitrate toxicity in freshwater rainbow trout (Oncorhynchus mykiss) is inhibition of gill Na+ and Cl- transport. Aquatic Toxicology 38: 145-163.

Pelgrom, S.M.G.J., Lock, R.A.C., Balm, P.H.M., Wendelaar Bonga, S.E. 1995. Integrated physiological response of tilapia, Oreochromis mossambicus, to sublethal copper exposure. Aquatic Toxicology 32: 303-320.

NOTE: Italics indicate edits from John Frisch September 2024