API

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Relationship: 3351

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

NTE, inhibited leads to LPS, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
NTE, inhibited
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
LPS, 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 Moderate 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 Do not cite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 High 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 Do not cite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
Mus musculus Mus musculus 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

While it was known that NTE could catalyze hydrolysis reactions it was unknown what the endogenous substrate was in animals and people. Recombinant human NTE expression in Escherichia coli of the functional domain NEST, which includes the catalytic domain of the enzyme, led to the initial discovery that NTE is capable of hydrolyzing several naturally occurring membrane-associated lipids. From this research came the hypothesis that NTE could be a lysophospholipase (Atkins & Glynn, 2000; van Tienhoven, Atkins, Li, & Glynn, 2002).

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

Confirmation that lysolecithin is an endogenous substrate for NTE resulted from in vivo and in vitro studies using mice and mouse brain homogenates, respectively, in a modified version of the original NTE inhibition assay which replaced the traditional artificial phenyl valerate substrate that had been used up until that point with LPC as the substrate. Similar rates of inhibition were measured with both the traditional and altered NTE assays following organophosphate exposure, indicating that NTE is capable of efficiently hydrolyzing LPC and led to the conclusion that not only is LPC a preferential substrate for NTE, but proposed that inhibition of the enzyme would cause LPC accumulation with detrimental effects to the nervous system (Quistad, Barlow, Winrow, Sparks, & Casida, 2003). These results were confirmed to be relevant to human NTE enzymes in a study investigating a new full-length recombinant human NTE transfected into the Nuero-2a mouse neuroblast and COS-7 primate kidney fibroblast-like cell lines which showed that human NTE efficiently hydrolyzes LPC as a biologically significant endogenous substrate (Vose, et al., 2008).

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

Nevertheless, there is general support for the feasibility of this KER in regards to the biological plausibility of the relationship, based on widespread evidence that if the function of an enzyme is inhibited, its endogenous substrate will accumulate because there is reduced action upon it to be broken down (Park & Kitteringham, 1990). The above outlined studies further support that LPC substrate accumulation in nervous tissue may occur following NTE inhibition.

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

Despite these indications that NTE inhibition increases LPC concentrations in a variety of in vitro and in vivo studies, some reports of orally administered TOCP in hens and mice indicated that while NTE inhibition was clearly observed, the levels of LPC were not significantly altered. This data was contradictory to what was hypothesized in these studies, and it was noted that this may have been due to feedback mechanisms in vivo that either reduced LPC synthesis or activated alternate degradation pathways in response to the loss of NTE activity to maintain the LPC balance (Hou, Long, Wang, Wang, & Wu, 2008; Hou, Long, & Wu, 2009).

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

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

Atkins, J., & Glynn, P. (2000). Membrane Association of and Critical Residues in the Catalytic Domain of Human Neuropathy Target Esterase. Journal of Biological Chemistry, 275(32), 24477-24483.

Hou, W.-Y., Long, D.-X., & Wu, Y.-J. (2009). The Homeostasis of Phosphatidylcholine and Lysophosphatidylcholine in Nervous Tissues of Mice was not Disrupted after Administration of Tri-o-cresyl Phosphate. Toxicological Sciences, 109(2), 276–285.

Hou, W.-Y., Long, D.-X., Wang, H.-P., Wang, Q., & Wu, Y.-J. (2008). The homeostasis of phosphatidylcholine and lysophosphatidylcholine was not disrupted during tri-o-cresyl phosphate-induced delayed neurotoxicity in hens. Toxicology, 252(1-3), 56-63.

Park, B. K., & Kitteringham, N. R. (1990). Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications. Xenobiotica, 20(11), 1171-1185.

Quistad, G. B., Barlow, C., Winrow, C. J., Sparks, S. E., & Casida, J. E. (2003). Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proceedings of the National Academy of Sciences, 100(13), 7983-7987.

van Tienhoven, M., Atkins, J., Li, Y., & Glynn, P. (2002). Human Neuropathy Target Esterase Catalyzes Hydrolysis of Membrane Lipids. Journal of Biological Chemistry, 277(23), 20942-20948.

Vose, S. C., Fujioka, K., Gulevich, A. G., Lin, A. Y., Holland, N. T., & Casida, J. E. (2008). Cellular function of neuropathy target esterase in lysophosphatidylcholine action. Toxicology and Applied Pharmacology, 232(3), 376-383.