This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 539

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

Decreased Sodium/Potassium ATPase activity leads to Heart failure

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Decreased Na/K ATPase activity leads to Heart failure
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: Kevin V. Brix, EcoTox and University of Miami; Gudrun De Boeck, University of Antwerp; Stijn Baken, European Copper Institute; and Douglas J. Fort, Fort Environmental Labs.

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 November 20, 2024 13:43

Revision dates for related pages

Page Revision Date/Time
Decreased Na/K ATPase activity December 03, 2024 10:12
Decreased, Sodium uptake in gills December 03, 2024 10:12
Decreased, Plasma sodium concentrations December 03, 2024 10:13
Increased, Blood viscosity December 03, 2024 10:14
Increased, Cardiac stress December 03, 2024 10:15
Heart failure December 03, 2024 10:15
Decreased, blood plasma volume December 03, 2024 10:14
Decreased Na/K ATPase activity leads to Decreased, sodium uptake in gills December 03, 2024 10:16
Decreased, sodium uptake in gills leads to Decreased, Plasma sodium concentrations December 03, 2024 10:16
Decreased, Plasma sodium concentrations leads to Decreased, blood plasma volume December 03, 2024 10:23
Decreased, blood plasma volume leads to Increased, Blood viscosity December 03, 2024 10:25
Increased, Blood viscosity leads to Increased, Cardiac stress December 03, 2024 10:18
Increased, Cardiac stress leads to Heart failure December 03, 2024 10:19
Heavy metals (cadmium, lead, copper, iron, nickel) October 25, 2021 03:21

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

Sodium is an abundant ion in blood plasma which requires active transport against its electrochemical gradient by sodium/potassium (Na/K) ATPase in order for uptake to occur in gills from the surrounding freshwater environment.  Disruption of sodium/potassium ATPase activity leads to a decrease in sodium uptake, and decrease in sodium blood plasma concentrations, resulting in disruption of osmoregulation.

Osmoregulation is a process in which organisms control fluid volume and concentration of ions.  Organisms use active transport and diffusion to regulate ion concentrations through intake rates, and through ion concentrations and reabsorption during excretion.  When fluid volume decreases, or blood components such as red blood cells, white blood cells, and blood proteins increase, blood viscosity increases.

This adverse outcome pathway focuses on the consequences of disruption of osmoregulation through disruption of sodium concentrations.  Increased blood viscosity causes increased cardiac stress due to increased resistance to flow through increased blood thickness and increased probability of aggregation of red blood cells and other blood components.   Cardiac stress manifests in increased heart rate and blood pressure, as well as decreased stroke volume, increasing the probability of heart failure.  

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: 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.   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 integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).   Brix et al. (2022) provided network analysis focused on mechanisms of action for copper toxicity in aquatic vertebrates through literature searches.  Literature searches provided the following mechanisms of copper toxicity: disruption of ion regulation; oxidative stress; effects on liver metabolism; effects on bioenergetics leading to impaired growth and reproduction; effects on sensory systems; effects on amphibian metabolism.  These mechanisms were the basis for examining empirical studies for development of key events and key event relationships within an adverse outcome pathway framework.  Freshwater organisms are hypertonic (higher ion concentration) compared to the aquatic environment while salt-water organisms are hypotonic (lower ion concentration) compared to the aquatic environment; therefore osmoregulation in freshwater organisms versus salt-water organisms regulate ion concentrations and fluid volumes in opposite directions.  Decrease in Sodium/Potassium ATPase activity and the resulting adverse outcome pathway were observed in freshwater vertebrates, primarily fish (Brix et al. 2022).

The authors of AOP 539 focused on disruption of ion regulation as the priority adverse outcome pathway to develop, because of the strength of  evidence linking the various key event relationships and the eventual adverse outcome.  

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 conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on toxicants known to disrupt osmoregulation in organisms. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself.   They then included all relevant publications through 2023. 

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 1562 Decreased Na/K ATPase activity Decreased Na/K ATPase activity
KE 2236 Decreased, Sodium uptake in gills Decreased, sodium uptake in gills
KE 2237 Decreased, Plasma sodium concentrations Decreased, Plasma sodium concentrations
KE 2261 Decreased, blood plasma volume Decreased, blood plasma volume
KE 2238 Increased, Blood viscosity Increased, Blood viscosity
KE 2239 Increased, Cardiac stress Increased, Cardiac stress
AO 1535 Heart failure Heart failure

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 High

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.

Relationship 3287: Decreased Na/K ATPase activity to Decreased, sodium uptake in gills

Strong support.  The relationship between decreased Na/K ATPase activity and decreased sodium uptake is broadly accepted and consistently supported among freshwater fish.

Relationship 3288: Decreased, sodium uptake in gills to Decreased, plasma sodium concentration

Strong support.  The relationship between decreased sodium uptake and decreased sodium plasma concentration is broadly accepted and consistently supported among freshwater fish.

Relationship 3346: Decreased, plasma sodium concentration to Decreased, blood plasma volume

Strong support. The relationship between decreased sodium plasma concentration and decreased blood plasma volume is broadly accepted and consistently supported among freshwater fish.

Relationship 3347: Decreased, blood plasma volume to Increased, blood viscosity

Strong support.  The relationship between increased decreased blood plasma volume and increased blood viscosity is broadly accepted and consistently supported among freshwater fish.

Relationship 3291: Increased, blood viscosity to Increased, Cardiac stress

Strong support.  The relationship between increased blood viscosity and increased cardiac stress is broadly accepted and consistently supported among freshwater fish.

Relationship 3292: Increased, Cardiac stress to Heart failure

Strong support.  The relationship between increased cardiac stress and heart failure is broadly accepted and consistently supported among freshwater fish.

Overall

Strong support.  Extensive understanding of the relationships between events from empirical studies from freshwater fish.

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 after heart formation and gill formation; not specific to any life stage.

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

Taxonomic: Freshwater true chordates - evidence primarily from fish.

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 = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events.

KE 1562 Decreased Na/K ATPase activity

Strong support.  Decreased Na/K ATPase activity is linked to decreased sodium uptake.  Evidence is available from toxicant, membrane studies examining the flow of molecules across membranes, and flow chamber studies measuring the uptake of ions from a known quantity in a container.  Best evidence for essentiality of Na/K ATPase activity is in membrane studies in which inhibition of Na/K ATPase activity leads to decreased sodium uptake, with normal Na/K ATPase activity and sodium uptake maintained in the absence of stressor.

KE 2236 Decreased, sodium uptake in gills

Moderate support.  Decreased sodium uptake is linked to decreased sodium plasma concentration.   Evidence is available from toxicant, membrane studies examining the flow of molecules across membranes, and flow chamber studies measuring the uptake of ions from a known quantity in a container.  Best evidence for essentiality of sodium uptake is in flow chamber studies in which decreased sodium uptake leads to decreased sodium plasma concentrations, with normal sodium uptake and plasma sodium concentration maintained in the absence of stressor.

KE 2237 Decreased, plasma sodium concentration

Moderate support.  Decreased sodium plasma concentration is linked to decreased blood plasma volume.  Evidence is available from toxicant and other stressor studies.  Best evidence for the essentiality of sodium plasma concentrations is in stressor studies in which decrease in sodium concentrations results in decreased blood plasma volume.  Sodium is an important blood component, but decreased blood osmolality from decrease of other ions can be expected to cause the same effect.

KE 2261 Decreased, blood plasma volume

Strong support. Decreased blood plasma volume is linked to blood viscosity.  Evidence is available from toxicant and other chronic stressor studies.  As osmoregulation has fluid volume and solute concentration components, loss of fluid volume or increased blood components such as red blood cells, white blood cells, and blood proteins results in increased blood viscosity.  Change in blood vessel diameter can help compensate for decreased blood plasma volume and mitigate potential effects on blood viscosity.

KE 2238 Increased, blood viscosity

Moderate support. Increased blood viscosity is linked to cardiac stress.  Evidence is available from toxicant and other stressor studies.  Increased blood viscosity results in increased cardiac stress because of increased resistance to flow.  Increased blood viscosity is only one factor leading to cardiac stress, which can be induced by inflammation, atherosclerosis, and other events.

KE 2239: Increased, Cardiac stress

Strong support.  Increased cardiac stress is linked to heart failure.  Evidence is available from physical activity and other chronic stressor studies.  Cardiac stress results in increased blood pressure, heart rate, and decreased stroke volume, with increased probability of heart failure.

KE 1535 Heart failure

This is the final event of the AOP.

Overall

Moderate to strong support.  Direct evidence from empirical studies from animals for most key events, with more inferential evidence for events occurring in cells and tissues.

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 3287: Decreased Na/K ATPase activity to Decreased, sodium uptake in gills

Strong support.  Decreased Na/K ATPase activity leads to decreased sodium uptake from membrane and flow chamber studies, as well as decreases in enzyme activity after exposure to chemical stressors.  Decreased Na/K ATPase activity occurred earlier in the time-course of exposure than decreased sodium uptake in gills, and the concentrations that decreased Na/K ATPAse activity were equal to or lower than the concentrations that decreased sodium uptake in gills.  Therefore, the data support a causal relationship.

Relationship 3288: Decreased, sodium uptake in gills to Decreased, plasma sodium concentration

Strong support. Decreased sodium uptake leads to decreased sodium plasma concentrations from membrane and flow chamber studies, as well as decreases in sodium plasma concentrations after exposure to chemical stressors.  Decreased sodium uptake in gills occurred earlier in the time-course of exposure than decreased plasma sodium concentration, and the concentrations that decreased sodium uptake in gills were equal to or lower than the concentrations that decreased plasma sodium concentration.  Therefore, the data support a causal relationship.

Relationship 3346: Decreased, plasma sodium concentration to Decreased, blood plasma volume

Strong support. Decreased sodium plasma concentration leads to decreased blood plasma volume through measurement of ion levels, from toxicant and other stressor studies.  Decreased plasma sodium concentration occurred earlier in the time-course of exposure than decreased blood plasma volume, and the concentrations that decreased plasma sodium concentration were equal to or lower than the concentrations that decreased blood plasma volume.  Therefore, the data support a causal relationship.

Relationship 3347: Decreased, blood plasma volume to Increased, blood viscosity

Strong support. Decreased blood plasma volume leads to increased blood viscosity due to loss of fluid volume or increased blood components, from toxicant and other stressor studies.  Decreased blood plasma volume occurred earlier in the time-course of exposure than increased blood viscosity, and the concentrations that decreased blood plasma volume were equal to or lower than the concentrations that increased blood viscosity.  Therefore, the data support a causal relationship.

Relationship 3291: Increased, blood viscosity to Increased, Cardiac stress

Strong support.  Increased blood viscosity leads to increased cardiac stress because of increased resistance to flow, from physical activity and other chronic stressor studies.  Increased blood viscosity occurred earlier in the time-course of exposure than increased cardiac stress, and the concentrations that increased blood viscosity were equal to or lower than the concentrations that increased cardiac stress.  Therefore, the data support a causal relationship.

Relationship 3292: Increased, Cardiac stress to Heart failure

Strong support.  Increased cardiac stress leads to heart failure through increased demand resulting in increased blood pressure, heart rate, and decreased stroke volume, from physical activity and other chronic stressor studies.  Increased cardiac stress occurred earlier in the time-course of exposure than heart failure, and the concentrations that increased cardiac stress were equal to or lower than the concentrations for heart failure.  Therefore, the data support a causal relationship.

Overall

Strong support. Evidence from empirical studies shows consistent change in both events from a variety of animal taxa, 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
     

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

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.