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AOP: 535

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

Inhibition of neuropathy target esterase leading to delayed neuropathy via lysolecithin cell membrane integration

Short name
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Inhibition of NTE leading to delayed neuropathy via LPS cell membrane integration
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 v2.6

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Of the originating work:

Brooke Bowe

Of the content populated in the AOP-Wiki:

Travis Karschnik (General Dynamics Information Technology, Duluth, MN, USA.)

Point of Contact

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Travis Karschnik   (email point of contact)

Contributors

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  • Travis Karschnik

Coaches

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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 September 27, 2024 15:38

Revision dates for related pages

Page Revision Date/Time
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

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

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

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

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

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

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

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 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)

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

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
Mus musculus Mus musculus NCBI
Homo sapiens Homo sapiens NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific

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

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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

Table 1: Overall assessment of the evidence supporting the AOP considering the essentiality of each key event (KE).

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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 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

Antonelli, M., & Kushner, I. (2017). It's time to redefine inflammation. The FASEB Journal, 31(5), 1787-1791.

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.

Buntinx, M., Moreels, M., Vandenabeele, F., Lambrichts, I., Raus, J., Steels, P., . . . Ameloot, M. (2004). Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-γ and TNF-α on apoptosis. Journal of Neuroscience Research, 76(6), 834-845.

Clothier, B., & Johnson, M. K. (1979). Rapid Aging of Neurotoxic Esterase after Inhibition by Di-isopropyl Phosphorofluoridate. Biochemical Journal, 177(2), 549-558.

Clothier, B., & Johnson, M. K. (1980). Reactivation and Aging of Neurotoxic Esterase Inhibited by a Variety of Organophosphorus Esters. Biochemical Journal, 185(3), 739-747.

Di Penta, A., Moreno, B., Reix, S., Fernandez-Diez, B., Villanueva, M., Errea, O., . . . Villoslada, P. (2013). Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation. PLOS One, 8(2), e54722.

Eaton, D. L., Daroff, R. B., Autrup, H., Bridges, J., Buffler, P., & Costa, L. G. (2008). Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment. Critical Reviews in Toxicology, 38(sup2), 1-125.

Ehrich, M., & Jortner, B. S. (2002). Organophosphate-Induced Delayed Neuropathy. In E. J. Massaro, Handbook of Neurotoxicology (pp. 17–27). Totowa, NJ: Humana Press.

Faria, M., Fuertes, I., Prats, E., Abad, J. L., Padrós, F., Gomez-Canela, C., . . . Raldúa, D. (2018). Analysis of the neurotoxic effects of neuropathic organophosphorus compounds in adult zebrafish. Scientific Reports, 8, 4844.

Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2000). Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chemistry and Physics of Lipids, 106(1), 1-29.

Göbel, K., Melzer, N., Herrmann, A. M., Schuhmann, M. K., Bittner, S., Ip, C. W., . . . Wiendl, H. (2010). Collateral Neuronal Apoptosis in CNS Gray Matter. Glia, 58(4), 469-480.

Haanen, C., & Vermes, I. (1995). Apoptosis and inflammation. Mediators of Inflammation, 4, 5-15.

He, W., Ding, J., Gao, N., Zhu, L., Zhu, L., & Feng, J. (2024). Elucidating the toxicity mechanisms of organophosphate esters by adverse outcome pathway network. Archives of Toxicology, 98, 233–250.

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.

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.

Inoue, K., & Kitagawa, T. (1974). Effect of exogenous lysolecithin of liposomal membranes its relation to membrane fluidity. Biochimica et Biophysica Acta, 363(3), 361-372.

Johnson, M. K. (1974). The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphorus esters. Journal of Neurochemistry, 23(4), 785–789.

Jokanović, M., Kosanović, M., Brkić, D., & Vukomanović, P. (2011). Organophosphate induced delayed polyneuropathy in man: an overview. Clinical Neurology and Neurosurgery, 113(1), 7-10.

Liu, P., Zhu, W., Chen, C., Yan, B., Zhu, L., Chen, X., & Peng, C. (2020). The mechanisms of lysophosphatidylcholine in the development of diseases. Life Sciences, 247, 117443.

Lowe, F. J., Luettich, K., Talikka, M., Hoang, V., Haswell, L. E., Hoeng, J., & Gaca, M. D. (2017). Development of an Adverse Outcome Pathway for the Onset. Applied In Vitro Toxicology, 3(1), 131-148.

McMurran, C. E., Zhao, C., & Franklin, R. J. (2019). Toxin-Based Models to Investigate Demyelination and Remyelination. In D. A. Lyons, & L. Kegel, Oligodendrocytes: Methods and Protocols (pp. 377–396). Springer.

Merwin, S. J., Obis, T., Nunez, Y., & Re, D. B. (2017). Organophosphate neurotoxicity to the voluntary motor system on the trail of environment-caused amyotrophic lateral sclerosis: the known, the misknown, and the unknown. Archives of Toxicology, 91, 2939–2952.

Ohno, N., & Ikenaka, K. (2019). Axonal and neuronal degeneration in myelin diseases. Neuroscience Research, 139, 48-57.

Ousman, S. S., & David, S. (2001). MIP-1α, MCP-1, GM-CSF, and TNF-α Control the Immune Cell Response That Mediates Rapid Phagocytosis of Myelin from the Adult Mouse Spinal Cord. The Journal of Neuroscience, 21(13), 4649–4656.

Pannu, A. K., Bhalla, A., Vishnu, R. I., Dhibar, D. P., Sharma, N., & Vijayvergiya, R. (2020). Organophosphate induced delayed neuropathy after an acute cholinergic crisis in self-poisoning. Clinical Toxicology, 59(6), 488-492.

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