API

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Relationship: 1775

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

endocytosis leads to Disruption, Lysosome

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
endocytosis
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Disruption, Lysosome

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
Endocytic lysosomal uptake leading to liver fibrosis adjacent High Allie Always (send email) Under development: Not open for comment. Do not cite EAGMST Under Review

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
human Homo sapiens NCBI
mouse Mus musculus NCBI
rat Rattus norvegicus NCBI
Hamster Hamster NCBI

Sex Applicability

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

Life Stage Applicability

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

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

Different substances can be uptaken by endocytosis and localized in lysosomes, while some of them can cause lysosomal disruption. Lysosomotropic agents are mostly weak, lipophilic bases that diffuse across lysosomal membrane, get protonated in the acidic milieu of lysosome and therefore get trapped inside (de Duve et al., 1974). They accumulate and cause the destabilization of lysosomal membranes by acting as surfactants, incorporating its hydrophobic tail in the membrane and with the hydrophilic head facing the interior of the lysosome (de Duve et al.,1974; Firestone et al.,1979). Their accumulation increase the intralysosomal pH, which has many consequences, including the prevention of the further uptake of lysosomotropic compounds, an increase in size and number of lysosomes and the overloading of lysosomes with non-digestible materials. 

There are different mechanisms how lysosomotropic agents can disrupt lysosomal membrane. However, not all lysosomotropic agents disrupt lysosomes- for example ammonia salts, methylamine and related hydrophilic weak bases cause swelling of the lysosomes, but do not increase permeability of the membrane. Usually in order to do that, agent requires a certain degree of lipid solubility. The amine will accumulate in the lysosomes until its concentration is high enough to solubilize the lysosomal membrane (Dubowchik et al., 1995)

It has been demonstrated that as a result of protonated agents in lysosomes, there will be accumulation of non-permeable charged substances which will result in inflow of water by increased osmolarity (Bandyopadhyay et al., 2014). Inflow of water results in increase of size and can cause the rupture of lysosome.

Also, oxidative stress can cause destabilization of the lysosomal membrane and for this process, intra-lysosomal ferric ions are essential. They catalyse the formation of oxygen radicals from hydrogen peroxide (Zdoslek et al., 1993).

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

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

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

Mouse (Werneburg et al., 2002; Kagedal et al., 2001)

Rat (Jung et al., 2015)

Hamster (Hayashi et al., 2008)

Human (Wang et al., 2013)