Neuropathy target esterase, inhibited

56-38-2

LCCNCVORNKJIRZ-UHFFFAOYSA-N

Parathion

Diethyl O-p-nitrophenyl phosphorothioate Phosphorothioic acid, O,O-diethylO-(4-nitrophenyl) ester Alleron American Cyanamid 3422 Aphamite Bayer E-605 Bladan F Diethyl 4-nitrophenyl phosphorothioate Diethyl parathion Diethyl p-nitrophenyl phosphorothionate Diethyl p-nitrophenyl thionophosphate Ethyl parathion Folidol Folidol E Folidol E-605 Folidol oil Fosferno Gearphos Lirothion Nitrostigmine Nourithion NSC 8933 O,O-Diethyl O-(4-nitrophenyl) phosphorothioate O,O-Diethyl O-(p-nitrophenyl) phosphorothioate O,O-Diethyl O-p-nitrophenyl thiophosphate O,O-Diethyl-O-(4-nitrophenyl)phosphorothioate Oleoparathene Oleoparathion Paraphos Parathene Parathion [Phosphorothioic acid, O,O-diethyl-O-(4-nitrophenyl)ester] Parathion A Parathion-ethyl paration Penncap E Phosphorothioic acid O,O-diethyl O-(4-nitrophenyl)ester Phosphorothioic acid, O,O-diethyl O-(4-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl)ester Rhodiasol Rhodiatox Selephos Super Rodiatox Thiomex Thiophos Thiophos 3422 Ethylparathion

DTXSID7021100

96-64-0

GRXKLBBBQUKJJZ-UHFFFAOYNA-N

GRXKLBBBQUKJJZ-UHFFFAOYSA-N

Soman

Soman Phosphonofluoridic acid, methyl-, 1,2,2-trimethylpropyl ester 1,2,2-Trimethylpropoxyfluorophosphine oxide 1,2,2-Trimethylpropyl methylphosphonofluoridate 3,3-Dimethyl-n-but-2-yl methylphosphonofluoridate Methyl pinacolyl phosphonofluoridate Methyl pinacolyloxy phosphorylfluoride Methylphosphonofluoridic acid 1,2,2-trimethylpropyl ester Phosphine oxide, fluoromethyl(1,2,2-trimethylpropoxy)- Phosphonofluoridic acid, P-methyl-, 1,2,2-trimethylpropyl ester Pinacoloxymethylphosphoryl fluoride Pinacolyl methylfluorophosphonate

DTXSID2031906

PR:000012946

PR neuropathy target esterase

CHEBI:60479

CHEBI lysophosphatidylcholine

CL:0000128

CL oligodendrocyte

GO:0008219

GO cell death

MP:0000921

MP demyelination

HP:0007305

HP CNS demyelination

WIKI decreased

WIKI increased

Organophosphates Organophosphate

repeated exposure

2016-11-29T18:42:20

2016-11-29T21:20:01

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

Neuropathy target esterase, inhibited

NTE, inhibited

Molecular

This is an integral membrane protein found in both neural and non-neural tissues that has been highly conserved throughout evolution (van Tienhoven, Atkins, Li, & Glynn, 2002). Although the exact physiologic function of NTE is still not fully understood, this serine hydrolase appears to preferentially hydrolyze phospholipids and has been deduced to be a lysophospholipase (Wijeyesakere & Richardson, 2010; Quistad, Barlow, Winrow, Sparks, & Casida, 2003). It’s function in nervous tissue is believed to be involved in axonal maintenance and membrane lipid homeostasis and thus its disruption can lead to negative downstream neurological effects (Eskut & Koskderelioglu, 2021; Read, Li, Chao, Cavanagh, & Glynn, 2009; Richardson, et al., 2020). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/10/01/8ny0umuyex_KE_NTE_inhibition.jpg" /> Figure 2: Two-step reaction of NTE inhibition and aging. In the upper reaction, binding of the chemical inhibits the enzyme via phosphorylation followed by an irreversible aging reaction that displaces an R group attached to oxygen (pathway of the “neurotoxic” organophosphates). In the lower reaction, the enzyme is inhibited but aging does not occur due to stability of the phosphorous-carbon bonds of the attached compound on the NTE (pathway of the “non-neurotoxic” organophosphates, carbamates, and sulphonates). Image adapted from: (Richardson, et al., 2020). Discovery of this enzyme was a direct product of the investigation on how organophosphates can lead to delayed neuropathy (Johnson, 1970). Preliminary studies looking at why only some organophosphates and related compounds cause OPIDN while others are unable to give rise to delayed neuropathy found that inhibition of the novel NTE enzyme occurs through a two-step process (figure 2). First, organophosphates and structurally similar chemicals are able to interact with the serine esterase domain of NTE via phosphorylation, greatly slowing down its rate of hydrolysis and making it essentially inhibited. The second step is an irreversible “aging” reaction in which the organophosphate loses an R group on an ester or amide bond, leaving behind a negatively charged phosphonyl group attached to the NTE which completes the inhibition (Johnson, 1974; Clothier & Johnson, 1979; Wijeyesakere & Richardson, 2010).

UBERON:0001016

UBERON nervous system

Not Specified Unspecific

<div> Clothier, B., & Johnson, M. K. (1979). Rapid Aging of Neurotoxic Esterase after Inhibition by Di-isopropyl Phosphorofluoridate. Biochemical Journal, 177(2), 549-558. Eskut, N., & Koskderelioglu, A. (2021). Neurotoxic Agents and Peripheral Neuropathy. In S. Sabuncuoglu, Neurotoxicity - New Advances. IntechOpen. Johnson, M. K. (1970). Organophosphorus and other inhibitors of brain 'neurotoxic esterase' and the development of delayed neurotoxicity in hens. Biochemical Journal, 120(3), 523–531. 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. 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. Read, D. J., Li, Y., Chao, M. V., Cavanagh, J. B., & Glynn, P. (2009). Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance. The Journal of Neuroscience, 29(37), 11594 –11600. Richardson, R. J., Fink, J. K., Glynn, P., Hufnagel, R. B., Makhaeva, G. F., & Wijeyesakere, S. J. (2020). Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN). In M. Aschner, & L. G. Costa, Advances in Neurotoxicology (Vol. 4, pp. 1-78). Academic Press. 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. Wijeyesakere, S. J., & Richardson, R. J. (2010). Neuropathy Target Esterase. In R. Krieger, Hayes' Handbook of Pesticide Toxicology (pp. 1435-1455). Academic Press. </div> AOPWiki 2024-10-01T12:34:22

2024-10-01T12:35:42

Lysolecithin, increased

LPS, increased

Cellular

<div> LPC is a mixture of various fatty acid tails that are the hydrolysis products of phospholipids (McMurran, Zhao, & Franklin, 2019). LPC has been noted to be distributed along cell membranes of many cell types (Sato, 1973; Lee & Chan, 1977; McMurran, Zhao, & Franklin, 2019). It has numerous physiologic functions across tissues, including roles in receptor binding (particularly G protein-coupled receptors and Toll-like receptors), ion channel activation, and as a chemoattractant for inflammatory molecules (Liu, et al., 2020; Hachem & Nacir, 2022). In addition, LPC is known to be able to promote demyelination and as a result has been widely used in vitro to study certain neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease (McMurran, Zhao, & Franklin, 2019; Liu, et al., 2020; Birgbauer, Rao, & Webb, 2004). LPC levels are regulated by the activity of numerous enzymes in the body. They are produced through phospholipase activity and eliminated by various lysophospholipases (Liu, et al., 2020; Quistad & Casida, 2004). Therefore, inhibition of some of these regulatory enzymes could cause alterations in the local concentration of LPC in tissues. </div>

Not Specified Unspecific Not Specified

<div> 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. Hachem, M., & Nacir, H. (2022). Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases. International Journal of Molecular Sciences, 23(7), 3969. Lee, Y., & Chan, S. I. (1977). Effect of Lysolecithin on the Structure and Permeability of Lecithin Bilayer Vesicles. Biochemistry, 16(7), 1303-1309. 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. 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. Quistad, G., & Casida, J. E. (2004). Lysophospholipase inhibition by organophosphorus toxicants. Toxicology and Applied Pharmacology, 196(3), 319-326. Sato, T. (1973). Variability in the Lysolecithin Content of Human Erythrocyte Membranes. Chemical and Pharmaceutical Bulletin, 21(1), 176-183. </div> AOPWiki 2024-10-01T12:37:21

2024-10-01T12:38:31

Lysolecithin cell membrane integration, increased

LPS cell membrane integration, increased

Cellular

Lysophospholipids, including LPC, are widely distributed signaling molecules that regularly interact with cellular membranes. While their presence helps maintain cellular function, usually only small amounts are found in the cell membrane itself (D’Arrigo & Servi, 2010). At high concentrations, however, lysophospholipids undergo increased incorporation into cell membranes which affects their integrity (Farooqui, Horrocks, & Farooqui, 2000; Tan, Ramesh, Toh, & Nguyen, 2020). LPC specifically has been shown to integrate into cell membranes of glial cells in the CNS when present at elevated levels, and that this accumulation can further lead to increased membrane permeability which is harmful to the cells (Elamrani & Blume, 1982; Plemel, et al., 2018).

Not Specified Unspecific Not Specified D’Arrigo, P., & Servi, S. (2010). Synthesis of Lysophospholipids. Molecules, 15(3), 1354–1377. Elamrani, K., & Blume, A. (1982). Incorporation Kinetics of Lysolecithin into Lecithin Vesicles. Kinetics of Lysolecithin-Induced Vesicle Fusion. Biochemistry, 21(3), 521-526. 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. 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. Tan, S. T., Ramesh, T., Toh, X. R., & Nguyen, L. N. (2020). Emerging roles of lysophospholipids in health and disease. Progress in Lipid Research, 80, 101068. AOPWiki 2024-10-01T12:39:12

2024-10-01T12:53:06

Oligodendrocyte death, increased

Cellular

Oligodendrocytes are the myelinating cells in the CNS (Arnett, et al., 2004). Myelination arises when extensions of the oligodendrocyte cell membrane, referred to as “processes”, repeatedly wrap around axons in the brain and spinal cord to create multi-layer sheaths (Baumann & Pham-Dinh, 2001). These critical glial cells provide protection to neurons and enhance neuronal signaling by increasing conduction velocity. In cases of disease or toxic insult, oligodendrocyte death can occur from a number of mechanisms. Common mechanisms that may contribute to cell death include pro-inflammatory cytokine death pathways, oxidative damage, elevation of the sphingomyelinase-ceramide pathway, and genetic alterations, among others (McTigue & Tripathi, 2008).

UBERON:0001016

UBERON nervous system

CL:0000128

CL oligodendrocyte

Not Specified Unspecific Not Specified

Arnett, H. A., Fancy, S. P., Alberta, J. A., Zhao, C., Plant, S. R., Kaing, S., . . . Stiles, C. D. (2004). bHLH Transcription Factor Olig1 is Required to Repair Demyelinated Lesions in the CNS. Science, 306(5704), 2111-2115. Baumann, N., & Pham-Dinh, D. (2001). Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System. Physiological Reviews, 81(2), 871-927. McTigue, D. M., & Tripathi, R. B. (2008). The life, death, and replacement of oligodendrocytes in the adult CNS. Journal of Neurochemistry, 107(1), 1-19. AOPWiki 2024-10-01T12:54:17

2024-10-01T12:55:40

Demyelination, increased

Cellular

<div> Demyelination is defined by the loss of myelin sheaths in nervous tissue, typically following insult from injury or disease. Demyelination is initiated by fractioning of myelin lamellae followed by removal of the fragments by proteolytic and lipolytic enzymes that can digest the myelin pieces (Cuzner & Norton, 1996; Höftberger & Lassmann, 2017). Considering myelin functions to maintain axon functionality and survival, once myelin is lost neurodegeneration ensues (Ohno & Ikenaka, 2019).  Demyelinating lesions can occur anywhere within the CNS including on myelin surrounding axons of both sensory and motor neurons (Höftberger & Lassmann, 2017). </div>

UBERON:0001016

UBERON nervous system

Not Specified Unspecific Not Specified

<div> Cuzner, M. L., & Norton, W. T. (1996). Biochemistry of Demyelination. Brain Pathology, 6(3), 231-242. Höftberger, R., & Lassmann, H. (2017). Inflammatory demyelinating diseases of the central nervous system. Handbook of Clinical Neurology, 145, 263–283. Ohno, N., & Ikenaka, K. (2019). Axonal and neuronal degeneration in myelin diseases. Neuroscience Research, 139, 48-57. </div> AOPWiki 2024-10-01T12:56:46

2024-10-01T12:57:09

Delayed neuropathy, increased

Individual

Not Specified Unspecific Not Specified AOPWiki 2024-10-01T14:39:36

2024-10-01T14:39:36

<upstream-id>04984543-fc1d-4248-be5a-0eb78d77c319</upstream-id> <downstream-id>6eef1f66-5388-475c-b480-0f8014f05985</downstream-id> <div> 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). </div>

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.

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).

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.

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).

Not Specified Unspecific Not Specified Not Specified

<div> 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. </div> AOPWiki 2024-10-01T14:41:54

2024-10-01T14:47:30

<upstream-id>6eef1f66-5388-475c-b480-0f8014f05985</upstream-id> <downstream-id>0757310d-86bb-4b42-bfc8-3e4cbf5a4734</downstream-id> <div> Elevated local concentrations of LPC have been known to disrupt cell membrane integrity and cause cellular death. Studies have indicated a few means of this process, the first of which is through increased absorption into cell membranes (Plemel, et al., 2018; McMurran, Zhao, & Franklin, 2019). </div>

<div> 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. </div>

Studies on glial cells of the central nervous system (CNS) treated with fluorescent-tagged LPC have demonstrated rapid incorporation into the cellular membrane of oligodendrocytes, as can be viewed in figure 3 (Plemel, et al., 2018). While these effects were observed in both oligodendrocytes and astrocytes, it has been suggested that oligodendrocytes might be particularly vulnerable to this cellular membrane integration since other cell types are capable of metabolizing LPC and reducing local concentrations whereas oligodendrocytes have not been shown to do this (McMurran, Zhao, & Franklin, 2019). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/10/01/1utskg9if6_KER2_Figure_3_AOP535.png" /> Figure 3: Images of immature mouse oligodendrocyte cell cultures (A) incubated with Nile Red to detect oligodendrocyte cell membranes and (B) treated with fluorescent-tagged (TopFluor) to detect the fluorescent-tagged LPC. Imaging revealed rapid LPC incorporation into cell membranes. Image adapted from: (Plemel, et al., 2018).

<div> Lysolecithins are amphipathic molecules with a hydrophilic head and hydrophobic tail that share many similar properties to surfactants. Due to the structural similarity to membrane lipids, surfactants are able to incorporate themselves into cell membranes and reduce the surface tension leading to a disruption of the stability of the membrane (Parsi, 2015). This detergent effect is theorized to also be able to occur with LPC considering their shared physicochemical properties, and therefore has been a point of investigation on the mechanisms of LPC-induced nervous cell death. </div>

Not Specified Unspecific Not Specified

<div> 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. Parsi, K. (2015). Interaction of detergent sclerosants with cell membranes. Phlebology, 30(5), 306-315. 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. </div> AOPWiki 2024-10-01T14:42:03

2024-10-01T14:50:53

<upstream-id>0757310d-86bb-4b42-bfc8-3e4cbf5a4734</upstream-id> <downstream-id>8dfcc381-11da-4a94-a896-86dd314f54a2</downstream-id>

<div> Evidence from in vitro studies using glial cell lines have indicated that lipid disrupting properties of LPC is the driving force behind oligodendrocyte cell death following accumulation in oligodendrocyte cell membranes. In addition to measuring how fluorescent tagged LPC integrates into cell membranes, the study conducted by Plemel, et al. (2018) also monitored cell death and found that there was a strong correlation between the rate of LPC membrane integration and the rate of oligodendrocyte cell death. </div>

<div> While this effect in oligodendrocytes has only been explored in one study, research on liposomal membranes has indicated that lysolecithin can incorporate into membranes under a variety of conditions and the susceptibility of membrane to damage is related to its fluidity. Principally, it was shown that the introduction of LPC to membranes with limited motion due to the presence of proteins and other constituents in the membrane (which is the case with oligodendrocyte membranes) then the addition will cause excess strain that increases its susceptibility to damage (Inoue & Kitagawa, 1974). This sort of damage has further been observed in other cell types, supporting the plausibility of this damage in oligodendrocytes as well (Weltzien, 1979; Zhou, et al., 2006). </div>

<div> Further assessment found that while membrane integration appeared to readily occur, membrane disruption and cellular death only occured above critical LPC concentrations (Plemel, et al., 2018). </div>

Not Specified Unspecific Not Specified

<div> 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. 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. Weltzien, H. U. (1979). Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochimica et Biophysica Acta, 559(2-9), 259–287. Zhou, L., Shi, M., Guo, Z., Brisbon, W., Hoover, R., & Yang, H. (2006). Different Cytotoxic Injuries Induced by Lysophosphatidylcholine and 7-Ketocholesterol in Mouse Endothelial Cells. Endothelium, 13(3), 213–226. </div> AOPWiki 2024-10-01T14:42:17

2024-10-01T15:09:36

<upstream-id>8dfcc381-11da-4a94-a896-86dd314f54a2</upstream-id> <downstream-id>669117b3-6764-4ba3-abeb-684defef0e0e</downstream-id>

<div> 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). </div>

<div> 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. </div>

<div> 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). </div>

<div> 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). </div>

Not Specified Unspecific Not Specified

<div> 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. </div> AOPWiki 2024-10-01T14:42:27

2024-10-01T15:10:49

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Modified Marchi staining of spinal cord slices from hens administered the organophosphate chemicals diisopropyl fluorophosphate (DFP), mipafox, or TOCP orally or via subcutaneous injections noted that animals presenting with a late paralysis that occurred 2-3 weeks after exposure also had demyelinating lesions that were especially apparent in the spinal cord (Barnes & Denz, 1953). Further analysis of the most affected regions in the spinal cord track indicates that regions of demyelination correspond with nerve tracts of both sensory and motor nerves, which could help explain the presentation of symptoms. For example, as seen in figure 5A there is a concentration of demyelination around the posterior median fissure in a region thought to correspond to the gracile fasciculus in humans, which is a sensory spinal cord tract. Meanwhile figure 5B displays focused demyelination laterally in the spinocerebellar tract of hens, which corresponds to proprioception and motor functions and has homologous structures in humans (Barnes & Denz, 1953). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/10/01/20e9b756k3_KER5_FIGURE5_aop535.png" style="height:210px; width:624px" /> Figure 5: Marchi method staining for demyelination following organophosphate administration in hens, wherein dark stains represent demyelination. (A) Upper dorsal cord, showing demyelination of gracile fasciculus in posterior columns; (B) upper cervical cord, showing damaged fibers grouped in lateral columns. Image adapted from: (Barnes & Denz, 1953). Similar results were seen in studies using mallards orally administered the organophosphates ethyl p-nitrophenyl phenylphosphorothioate (EPN) or leptophos, which indicated that demyelinating lesions and clinical OPIDN symptoms are closely related. In this second study, evidence supporting the biological plausibility of this KER is notably apparent as the severity of demyelination has a linear relationship not only to the administered dose of EPN but also to the number of ducks exhibiting ataxia or paralysis.

<div> While no test animals displayed neuropathy symptoms at the lowest dose, this concentration was capable of producing barely detectable demyelination. At higher doses, delayed neuropathy was present in all test animals along with clear evidence of demyelination (Hoffman, Sileo, & Murray, 1984). This appears to suggest that demyelination occurs as a first step and at lower exposure doses before being followed by neuropathy at higher doses dependent upon the initial demyelination. </div>

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<div> Barnes, J. M., & Denz, F. A. (1953). Experimental demyelination with organo-phosphorus compounds. Journal of Pathology and Bacteriology, 65(2), 597-605. 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. </div> AOPWiki 2024-10-01T14:42:37

2024-10-01T15:25:16

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

Inhibition of NTE leading to delayed neuropathy via LPS cell membrane integration

Brooke Bowe

<div> Of the originating work: Brooke Bowe Of the content populated in the AOP-Wiki: Travis Karschnik (General Dynamics Information Technology, Duluth, MN, USA.) </div>

BY-SA

2.7

<div> 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. </div> <div> 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.  </div>

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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.

Table 1: Overall assessment of the evidence supporting the AOP considering the essentiality of each key event (KE). <table cellspacing="0" class="Table" style="border-collapse:collapse; width:100.0%"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:77px; vertical-align:top; width:18%"> KE </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:77px; vertical-align:top; width:28%"> KE description </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:77px; vertical-align:top; width:13%"> Support on the essentiality of the KE </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:77px; vertical-align:top; width:40%"> Defining question: are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:53px; vertical-align:top; width:18%"> MIE: Neuropathy target esterase, inhibited </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:53px; vertical-align:top; width:28%"> A 2-step inhibition of NTE blocks the enzyme’s lysophospholipase activity. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:53px; vertical-align:top; width:13%">  High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:53px; vertical-align:top; width:40%"> 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). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:18%"> KE1: Lysolecithin, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:28%"> LPC is endogenously found around cell membranes and can act as a chemoattractant for inflammatory cells. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:13%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:40%"> 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). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:52px; vertical-align:top; width:18%"> KE2: Lysolecithin cell membrane integration, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:52px; vertical-align:top; width:28%"> Integration into membranes increases as the local concentration of LPC raises. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:52px; vertical-align:top; width:13%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:52px; vertical-align:top; width:40%"> 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). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:18%"> KE3: Oligodendrocyte death, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:28%"> Inflammatory death pathways, oxidative damage, sphingomyelinase-ceramide pathways, and genetic alterations can contribute to cell death. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:13%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:40%"> Oligodendrocytes provide critical support to the nervous system and signal transduction pathways. Loss of this support leaves nervous tissue susceptible to damage (Birgbauer, 2004). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:18%"> KE4: Demyelination, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:28%"> Disintegration of myelin membranes which leaves axons exposure to injury and negatively impacts cell signaling. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:13%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:56px; vertical-align:top; width:40%"> 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). </td> </tr> <tr> <td style="border-bottom:3px double black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:38px; vertical-align:top; width:18%"> AO: Delayed neuropathy, increased </td> <td style="border-bottom:3px double black; border-left:none; border-right:1px solid black; border-top:none; height:38px; vertical-align:top; width:28%"> Delayed neuropathy presents with both sensory and motor symptoms, and is a result of damage to numerous structures including axons and myelin. </td> <td style="border-bottom:3px double black; border-left:none; border-right:1px solid black; border-top:none; height:38px; vertical-align:top; width:13%"> High </td> <td style="border-bottom:3px double black; border-left:none; border-right:1px solid black; border-top:none; height:38px; vertical-align:top; width:40%"> 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). </td> </tr> </tbody> </table>

Table 2: Containing the biological plausibility and empirical support for each key event relationship (KER). <table cellspacing="0" class="Table" style="border-collapse:collapse; width:100.0%"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:3px double black; height:93px; vertical-align:top; width:18%"> KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:3px double black; height:93px; vertical-align:top; width:13%"> Support for biological plausibility of the KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:3px double black; height:93px; vertical-align:top; width:28%"> Defining question: Is there a mechanistic (i.e. structural or functional) relationship between KEup and KEdown consistent with established biological knowledge? </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:3px double black; height:93px; vertical-align:top; width:12%"> Empirical support for the KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:3px double black; height:93px; vertical-align:top; width:27%"> 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? </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:179px; vertical-align:top; width:18%"> (MIE) NTE, inhibited leads to (KE1) LPS, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:179px; vertical-align:top; width:13%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:179px; vertical-align:top; width:28%"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:179px; vertical-align:top; width:12%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:179px; vertical-align:top; width:27%"> 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). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:131px; vertical-align:top; width:18%"> (KE1) LPS, increased leads to (KE2) LPS cell membrane integration, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:131px; vertical-align:top; width:13%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:131px; vertical-align:top; width:28%"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:131px; vertical-align:top; width:12%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:131px; vertical-align:top; width:27%"> 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. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:2.2in; vertical-align:top; width:18%"> (KE2) LPS cell membrane integration, increased leads to (KE3) Oligodendrocyte death, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:2.2in; vertical-align:top; width:13%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:2.2in; vertical-align:top; width:28%"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:2.2in; vertical-align:top; width:12%"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:2.2in; vertical-align:top; width:27%"> 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. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:1.9in; vertical-align:top; width:18%"> (KE3) Oligodendrocyte death, increased leads to (KE4) Demyelination, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:1.9in; vertical-align:top; width:13%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:1.9in; vertical-align:top; width:28%"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:1.9in; vertical-align:top; width:12%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:1.9in; vertical-align:top; width:27%"> 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). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:167px; vertical-align:top; width:18%"> (KE4) Demyelination, increased leads to (AO) Delayed neuropathy, increased </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:167px; vertical-align:top; width:13%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:167px; vertical-align:top; width:28%"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:167px; vertical-align:top; width:12%"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:167px; vertical-align:top; width:27%"> 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). </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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