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AOP: 535
Title
Inhibition of neuropathy target esterase leading to delayed neuropathy via lysolecithin cell membrane integration
Short name
Graphical Representation
Point of Contact
Contributors
- Travis Karschnik
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on September 27, 2024 15:38
Revision dates for related pages
Page | Revision Date/Time |
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Neuropathy target esterase, inhibited | September 27, 2024 16:32 |
Lysolecithin, increased | September 13, 2024 14:41 |
Lysolecithin cell membrane integration, increased | September 13, 2024 14:56 |
Oligodendrocyte death, increased | September 27, 2024 16:33 |
Demyelination, increased | September 27, 2024 16:33 |
Delayed neuropathy, increased | September 06, 2024 16:18 |
NTE, inhibited leads to LPS, increased | September 26, 2024 18:21 |
LPS, increased leads to LPS cell membrane integration, increased | September 26, 2024 18:20 |
LPS cell membrane integration, increased leads to Oligodendrocyte death, increased | September 26, 2024 18:20 |
Oligodendrocyte death, increased leads to Demyelination, increased | September 26, 2024 18:20 |
Demyelination, increased leads to Delayed neuropathy, increased | September 26, 2024 18:21 |
Organophosphates | November 29, 2016 21:20 |
Abstract
Organophosphate pesticides remain a major concern for their neurotoxicity with many chemicals being restricted in their use worldwide. This AOP provides a valuable tool to help understand a possible mechanism contributing to delayed neuropathy which could aid in improving disease outcomes in those afflicted with OPIDN. Despite the support in essentiality, biological plausibility, and empirical evidence that is available, additional research could be made on establishing dose-response relationships between elevated LPC and cell membrane integration and improvement of the KER description between oligodendrocyte death and demyelination. These data would help characterize the relevancy of these molecular events to prevent full neuropathy progression and increase confidence in the relationships proposed throughout the AOP, establishing a series of KEs that could be used in subsequent AOP developments relating to neurotoxicity.
There are notable differences in the construction of this AOP compared to some of the major conclusions of mechanisms in the literature. Whereas many articles cite axonal degeneration as a primary pathway warranting investigation, this AOP focuses instead on the demyelinating lesions and how they contribute to disease progression (Faria, et al., 2018; Richardson, et al., 2020). Development of a parallel AOP investigating the molecular connections between NTE inhibition and the frequently described axonopathy merits further investigation and development of this AOP would help strengthen the overall understanding of disease progression in OPIDN. In general, the AOP described herein can, and should be, considered in the context of previously described AOP networks for organophosphate esters as a way to strengthen the neurotoxicity endpoint and begin to establish clear KEs, which is a major feature the current networks are lacking.
AOP Development Strategy
Context
OPIDN is a somewhat rare but serious disease with over 70,000 reported cases in the past century, although this is thought to be underestimated as there is a disproportionately high use of organophosphate pesticides in developing countries but over half of these reported cases came from the United States alone (Merwin, Obis, Nunez, & Re, 2017). When OPIDN does occur, delayed neuropathy can present in various degrees of severity with not only incredibly painful physical symptoms but also emotional distress as cramping and muscle pains progress to weakness and, in severe cases, paralysis. While some people make a full recovery from OPIDN, the residual sensory and autonomic dysfunction can last for years, and in some cases never recovers at all (Eaton, et al., 2008; Jokanović, Kosanović, Brkić, & Vukomanović, 2011). Ultimate prognosis is believed to be more dependent on CNS effects, with some cases even showing a worsening of symptoms over time rather than improvement (Jokanović, Kosanović, Brkić, & Vukomanović, 2011). Despite the severity of symptoms, there remains no specific treatment available for OPIDN patients (Faria, et al., 2018). Accordingly, there would be great benefit to understanding the molecular pathway of this disease as a possibility to develop preventative strategies or therapies that can mitigate symptoms and improve health outcomes.
Developments of AOP networks surrounding organophosphate esters have been previously proposed. In the last few years, a number of papers have been published attempting to devise extensive AOP networks on organophosphate compounds that include a variety of MIEs and AOs (Yan, et al., 2021; Wang, Li, Teng, Ji, & Wu, 2022; He, et al., 2024). However, these networks often have little to no focus on neurotoxicity and tend to focus more on differences between specific organophosphates leading to alternative AOs with underdeveloped or incomplete mechanisms linking initiating events and the various toxic endpoints. In most cases, there is a lack of a comprehensive KE pathway, no development of KERs, and no mention of NTE inhibition or the subsequent KEs outlined in the pathway that is proposed here. Aside from these above mentioned AOP networks, it has been noted previously that NTE inhibition is a widely accepted starting point for development of an AOP on OPIDN and that disruption of LPC homeostasis is likely involved (Faria, et al., 2018). While the creation of this AOP came from independent conclusions on the likely MIE and KEs, the conclusions expressed by Faria, et al. (2018) indicate that there is external support for the initial steps of this AOP.
Strategy
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.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 2243 | Neuropathy target esterase, inhibited | NTE, inhibited |
KE | 2244 | Lysolecithin, increased | LPS, increased |
KE | 2245 | Lysolecithin cell membrane integration, increased | LPS cell membrane integration, increased |
KE | 2246 | Oligodendrocyte death, increased | Oligodendrocyte death, increased |
KE | 2247 | Demyelination, increased | Demyelination, increased |
AO | 2248 | Delayed neuropathy, increased | Delayed neuropathy, increased |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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NTE, inhibited leads to LPS, increased | adjacent | Moderate | |
LPS, increased leads to LPS cell membrane integration, increased | adjacent | Moderate | |
LPS cell membrane integration, increased leads to Oligodendrocyte death, increased | adjacent | Moderate | |
Oligodendrocyte death, increased leads to Demyelination, increased | adjacent | High | |
Demyelination, increased leads to Delayed neuropathy, increased | adjacent | High |
Network View
Prototypical Stressors
Name |
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Organophosphates |
Life Stage Applicability
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
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Unspecific |
Overall Assessment of the AOP
Inhibition of esterase enzymes is widely understood to lead to neurotoxic outcomes. This is the case outlined in the above AOP linking NTE inhibition to delayed peripheral neuropathy, particularly in the context of organophosphate pesticide exposures causing OPIDN. The essentiality of each KE, biological plausibility of KER’s, and the available empirical evidence can each be considered to better assess the strength in this AOP (Tables 1 and 2). Ratings of each of these features were in accordance with previously established definitions used in other AOP developments (Lowe, et al., 2017). Briefly, essentiality was considered high with direct evidence, moderate with indirect evidence, and low with no or contradictory evidence of the KE. Biological plausibility and empirical support were considered high with extensive understanding of a KER or multiple studies showing changes, while moderate and low ratings relied on associations with analogous events with gaps or inconsistencies present.
The essentiality of the key events appears to be moderate to high throughout this pathway. The MIE and KE3 have notably strong essentiality as incomplete NTE activation or survival of oligodendrocytes and the myelin sheath clearly and consistently demonstrate a lack of delayed neuropathy development through this mechanism. While certain events such as KE1 are difficult to alter in a system replicable to the changes caused by the MIE, and KE2 lack any studies investigating its essentiality, the intermediate KE of inflammation also appears to show high essentiality. This can be concluded considering that blockage of the inflammatory response results in far less oligodendrocyte death and a near complete loss of demyelination.
One major strength of this AOP is the biological plausibility between each of the key events. The support of biological plausibility for each KER is considered moderate to high based on widely established and accepted understandings of these relationships. Further, certain relationships have a clear link based on basic physiology and general biological knowledge. For example, since myelin is part of the cellular membrane of oligodendrocytes, death of these cells will result in the subsequent demyelination since living cells are required to maintain this sheath. The foundation of the biological plausibility was further used to develop some intermediate steps of this AOP because, while limited research has been conducted on the full mechanisms of OPIDN, data on the mechanisms of related demyelinating diseases can be used to inform likely steps in the disease development from the MIE.
Most of the empirical evidence for the KERs in this AOP can be rated as moderate. Studies are available in both in vitro and in vivo models to demonstrate many of these KERs. In some cases, such as the relationship between the MIE and KE1, there is a large variety of evidence available although conflicting results have been seen on whether there is truly a change in LPC levels alongside NTE inhibition in vivo. However, the test methods employed vary drastically in the selected organophosphates, doses, and test animal species. Therefore, the lack of observed LPC changes could be attributed to either using an organophosphate with a lower propensity to cause OPIDN or because the animal models were less sensitive to disease development considering that it is known that there are substantial species differences in OPIDN progression. Many other KERs do have evidence indicating that changes in the upstream KE influence changes in the downstream KE, although often times there is only one or two studies available and there is a lack of any dose-response or temporal information in the relationship. In general, the beginning and end of the AOP have a collection of studies demonstrating how organophosphates and structurally similar chemicals can induce the MIE or final KE, Demyelination, increased, leading to delayed neuropathy. However, studies investigating how these compounds can lead to mid-point KEs are largely unavailable hindering widespread connections throughout the proposed AOP mechanism. In particular, the KER between oligodendrocyte death and demyelination lacks direct empirical support, however, the biological plausibility of the relationship is considered to be high which allows this KER to still be considered as a likely mechanism in the AOP.
Domain of Applicability
Essentiality of the Key Events
Table 1: Overall assessment of the evidence supporting the AOP considering the essentiality of each key event (KE). |
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KE |
KE description |
Support on the essentiality of the KE |
Defining question: are downstream KEs and/or the AO prevented if an upstream KE is blocked? |
MIE: Neuropathy target esterase, inhibited |
A 2-step inhibition of NTE blocks the enzyme’s lysophospholipase activity. |
High |
Repeated evidence that only compounds that undergo the both the inhibition and aging steps of NTE inhibition leads to OPIDN (Johnson, 1974; Clothier, 1979; Wijeyesakere, 2010). In cases where this second step does not occur, the characteristic delayed neuropathy of OPIDN does not present (Clothier, 1980). |
KE1: Lysolecithin, increased |
LPC is endogenously found around cell membranes and can act as a chemoattractant for inflammatory cells. |
Moderate |
Elevated LPC is known to be cytotoxic (McMurran, 2019; Liu, 2020). Modeling of this event has been scarce in experimental systems and while there is clear evidence of cell damage, the measured changes in LPC levels are inconsistent (Hou, 2008; Hou, 2009). |
KE2: Lysolecithin cell membrane integration, increased |
Integration into membranes increases as the local concentration of LPC raises. |
Moderate |
Although LPC integration into membranes has been shown to be able to occur, it has not yet been established whether neuropathy is hindered by blocking this event (Plemel, 2018). |
KE3: Oligodendrocyte death, increased |
Inflammatory death pathways, oxidative damage, sphingomyelinase-ceramide pathways, and genetic alterations can contribute to cell death. |
High |
Oligodendrocytes provide critical support to the nervous system and signal transduction pathways. Loss of this support leaves nervous tissue susceptible to damage (Birgbauer, 2004). |
KE4: Demyelination, increased |
Disintegration of myelin membranes which leaves axons exposure to injury and negatively impacts cell signaling. |
High |
Demyelination is consistently observed in neuropathic conditions (McMurran, 2019). The presence of demyelinating lesions have been shown to directly correlate to the presentation of neuropathic symptoms in animal models (Barnes, 1953; Hoffman, 1984). |
AO: Delayed neuropathy, increased |
Delayed neuropathy presents with both sensory and motor symptoms, and is a result of damage to numerous structures including axons and myelin. |
High |
Final step which is the physiologic presentation of OPIDN (Jokanović, 2011; Pannu, 2020). Long-lasting symptoms are frequently tied to damage of axons and myelin, which are characteristic to this disease (Ehrich, 2002). |
Evidence Assessment
Table 2: Containing the biological plausibility and empirical support for each key event relationship (KER).
KER |
Support for biological plausibility of the KER |
Defining question: Is there a mechanistic (i.e. structural or functional) relationship between KEup and KEdown consistent with established biological knowledge? |
Empirical support for the KER |
Defining question: Does the empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses, earlier time points, and higher incidence than KEdown? |
(MIE) NTE, inhibited leads to (KE1) LPS, increased |
High |
It is well established that inhibition of an enzyme will cause local accumulation of its preferred substrate, as is the case with NTE and the demonstrated endogenous substrate LPC (Park, 1990; Quistad, 2003). |
Moderate |
Both mouse and recombinant NTE have been shown to be able to hydrolyze LPC. Further, the level of LPC can be measured in a dose-dependent manner to determine the level of NTE inhibition that is occuring (van Tienhoven, 2002; Quistad, 2003; Vose, 2008). However, some studies have not seen this relationship following organophosphate administration, although this could be due to animal and organophosphate species differences (Hou, 2008; Hou, 2009). |
(KE1) LPS, increased leads to (KE2) LPS cell membrane integration, increased |
Moderate |
There is wide acceptance that increased levels of LPC causes neurotoxicity, although the exact mechanism is still up for debate. Structural similarity to other surfactants indicates LPC can incorporate into cell membranes and disrupt the stability (Parsi, 2015; McMurran, 2019). |
Moderate |
Evidence is available from in vitro studies showing clear integration into cell membranes following lysolecithin application (Plemel, et al., 2017). However, there is a limited number of available studies and a lack of dose-response data on lysolecithin levels and rate of membrane incorporation. |
(KE2) LPS cell membrane integration, increased leads to (KE3) Oligodendrocyte death, increased |
Moderate |
Investigations on general liposomal membranes have shown that high concentrations of lysolipids and phospholipids can lead to membrane integration (Farooqui, 2000). High levels of incorporation can increase membrane strain and is associated with cellular instability (Inoue, 1974). LPC specifically has demonstrated evidence of membrane integration in other cellular types, including erythrocyte and endothelial cells (Weltzien, 1979; Zhou, 2006). |
Moderate |
The rate of LPC cell membrane incorporation has been shown to closely correlate to the rate of oligodendrocyte death in in vitro testing, with evidence that KE4 only occurs once KE2 reaches a critical level (Plemel, 2018). The lack of studies investigating this relationship, however, lowers the rating of empirical support. |
(KE3) Oligodendrocyte death, increased leads to (KE4) Demyelination, increased |
High |
It is widely accepted that overstimulation of the inflammatory response can cause tissue damage as the immune system inappropriately targets self-cells when rampant inflammation occurs (Antonelli, 2017; Haanen, 1995; van der Oever, 2010; Göbel, 2010). |
High |
Studies in cell lines and animal models have repeatedly shown that elevated levels of cytokines and leukocytes can each act directly on oligodendrocytes to instigate cell death (Patel, 2012; T cell-mediated cytotoxicity, 2001; Buntinx, 2004; Shi, 2015; Ousman, 2001). Further, studies have shown that inhibition of the inflammatory response significantly decreases oligodendrocyte death, supporting that inflammation occurs prior to and leads to cell death (Di Penta, 2013). |
(KE4) Demyelination, increased leads to (AO) Delayed neuropathy, increased |
High |
It is widely understood that myelin is responsible for supporting the health and functionality of the CNS, and therefore demyelination can lead to a variety of neuropathic symptoms depending on the regions of the nervous sytem that suffer demyelinating lesions (Ohno, 2019). |
High |
Consistent evidence is available in numerous studies that demyelinating lesions are observed in animals suffering from the symptoms of delayed neuropathy during OPIDN. In addition to the number of studies observing this KER, there is a dose-response relationship between the MIE, KE5, and the AO both in severity of demyelination and the dose required for symptoms of the AO to appear (Barnes, 1953; Hoffman, 1984). |
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
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Quantitative Understanding
Considerations for Potential Applications of the AOP (optional)
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