API

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Relationship: 3354

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

Oligodendrocyte death, increased leads to Demyelination, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Oligodendrocyte death, increased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Demyelination, increased

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 of neuropathy target esterase leading to delayed neuropathy via lysolecithin cell membrane integration adjacent High Brooke Bowe (send email) Under development: Not open for comment. Do not cite
Inhibition of neuropathy target esterase leading to delayed neuropathy via increased inflammation adjacent Low Brooke Bowe (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 Do not cite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
Homo sapiens Homo sapiens 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

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

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

Literature reviews were conducted by searching through databases including PubMed and Google Scholar. Search terms included “organophosphates”, “OPIDN”, “OPIDP”, and “delayed neuropathy” used in combination with a variety of phrases such as “enzyme inhibition”, “demyelination”, “demyelinating lesions”, “weakness”, and “endogenous substrate.”  After establishment of the general outline for the AOP, search terms broadened to commonly include the words “neuropathy target esterase”, “irreversible aging”, “lysolecithin”, “lysophosphatidylcholine”, “inflammation”, “chemokines”, “surfactant”, “membrane disruption”, “oligodendrocyte susceptibility”, and “oligodendrocyte death.” Exclusion criteria included publications that focused on nervous tissue damage that did not involve changes to oligodendrocytes or myelin considering that this pathway focused on a single mechanism of a larger overall AOP network, and the goal was to specifically focus on progression of demyelination causing delayed neuropathy. Additional resources were also identified in the references of publications explored during database searches and were used to further develop KEs.

Evidence Supporting this KER

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

In many cases reduced oligodendrocyte counts overlaps closely with regions of demyelination following cellular imaging of in vitro tests (Felts, et al., 2005).  Once oligodendrocytes have been killed, their myelin membranes begin to disintegrate as well leaving axons of the CNS exposed and vulnerable to damage (Birgbauer, Rao, & Webb, 2004).

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

In many cases reduced oligodendrocyte counts overlaps closely with regions of demyelination following cellular imaging of in vitro tests (Felts, et al., 2005). This relationship is inherent because the myelin sheaths are a part of oligodendrocyte cell membranes, and therefore the health of the myelin is supported by the oligodendrocyte which it originates from (Höftberger & Lassmann, 2017). In this way, oligodendrocyte death can promote dysfunction of the nervous system through the subsequent loss of myelin sheaths along axons.

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

It is possible that demyelination can either originate from death of oligodendrocytes or from direct targeting of myelin itself. Elevated LPC and subsequent events have been largely identified as being able to act on the myelin by cell membrane integration leading some papers to conclude that LPC acts as a primary myelinotoxic compound (Duncan & Radcliff, 2016). However, more recent evidence has showed that the inflammatory response stimulated by LPC can instigate oligodendrocyte death directly as a contributor to the process of demyelination (Plemel, et al., 2018).

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
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

In reality, oligodendrocyte death and demyelination are likely happening simultaneously and perpetuating each other’s progression. Together, oligodendrocyte death and direct harm of myelin are monitored by overall demyelination patterns as a major hallmark of OPIDN toxicity leading to delayed neuropathy (Barnes & Denz, 1953; Hoffman, Sileo, & Murray, 1984; Wang, Yang, Jiang, & Wu, 2019).

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

References

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

Barnes, J. M., & Denz, F. A. (1953). Experimental demyelination with organo-phosphorus compounds. Journal of Pathology and Bacteriology, 65(2), 597-605.

Birgbauer, E., Rao, T. S., & Webb, M. (2004). Lysolecithin induces demyelination in vitro in a cerebellar slice culture system. Journal of Neuroscience Research, 78(2), 157-166.

Duncan, I. D., & Radcliff, A. B. (2016). Inherited and acquired disorders of myelin: The underlying myelin pathology. Experimental Neurology, 283, 452-475.

Felts, P. A., Woolston, A.-M., Fernando, H. B., Asquith, S., Gregson, N. A., Mizzi, O. J., & Smith, K. J. (2005). Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide. Brain, 128(7), 1649–1666.

Hoffman, D. J., Sileo, L., & Murray, H. C. (1984). Subchronic organophosphorus ester-induced delayed neurotoxicity in mallards. Toxicology and Applied Pharmacology, 75(1), 128-136.

Höftberger, R., & Lassmann, H. (2017). Inflammatory demyelinating diseases of the central nervous system. Handbook of Clinical Neurology, 145, 263–283.

Plemel, J. R., Michaels, N. J., Weishaupt, N., Caprariello, A. V., Keough, M. B., Rogers, J. A., . . . Yong, V. W. (2018). Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy. Glia, 66(2), 327-347.

Wang, P., Yang, M., Jiang, L., & Wu, Y.-J. (2019). A fungicide miconazole ameliorates tri-o-cresyl phosphate-induced demyelination through inhibition of ErbB/Akt pathway. Neuropharmacology, 148, 31-39.