Neuropathy target esterase in mouse whole blood as a biomarker of exposure to neuropathic organophosphorus compounds

Development of biomarkers of human exposures to organophosphorus compounds OPCs and their quantification is a vital component of a system of prediction and early diagnostics of OPC-induced diseases. Our study was focused on investigation of esterase status as a complex biomarker of exposure to OPCs and an aid in accurate diagnosis. We suggest that this complex biomarker should be more effective and informative than standard assays of plasma butyrylcholinesterase (BChE), erythrocyte acetylcholinesterase (RBC AChE), and lymphocyte neuropathy target esterase (NTE). It will help: 1) to assess an exposure as such and to confirm the nonexposure of individuals suspected to have been exposed; 2) to determine if the exposure was to agents expected to produce acute and/or delayed neurotoxicity; 3) to perform dosimetry of the exposure, which provides valuable information for medical treatment. To confirm this hypothesis, we have examined the changes in activity of blood AChE, NTE, BChE and carboxylesterase (CaE) 1 h after i.p. administration of increasing doses of three OPCs with different esterase profiles: the known neuropathic compound O,O-dipropyl-O-dichlorovinyl phosphate (C3H 7O)2P(O)OCH=CCl2 (diPr-DClVP) as the control compound and two model dialkylphosphates (C2H5O)2P(O)OCH(CF3)2 (diEt-PFP) and (C4H9O)2P(O)OCH(CF3)2 (diBu-PFP). The esterases assay was performed in hemolysed blood by spectrophotometric (AChE, BChE, CaE) and biosensor (NTE) methods. Analysis of the obtained dose-dependences for blood esterases inhibition showed that blood BChE and CaE were the most sensitive biomarkers, allowing detection of low doses. Inhibition of blood NTE and AChE can be used to assess the likelihood that an exposure to OPC would produce cholinergic and/or delayed neuropathic effects.

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Faculty Opinions recommendation of Biosensor assay of neuropathy target esterase in whole blood as a new approach to OPIDN risk assessment: review of progress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089895.543048 ◽

2007 ◽

Author(s):

David Baker

Keyword(s):

Risk Assessment ◽

Whole Blood ◽

Neuropathy Target Esterase ◽

New Approach

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Acetylcholinesterase and Neuropathy Target Esterase Inhibitions in Neuroblastoma Cells to Distinguish Organophosphorus Compounds Causing Acute and Delayed Neurotoxicity

Toxicological Sciences ◽

10.1093/toxsci/38.1.55 ◽

1997 ◽

Vol 38 (1) ◽

pp. 55-63 ◽

Cited By ~ 2

Author(s):

Marion Ehrich ◽

Linda Correll ◽

Bellina Veronesi

Keyword(s):

Organophosphorus Compounds ◽

Neuroblastoma Cells ◽

Neuropathy Target Esterase ◽

Delayed Neurotoxicity

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Review : Neuropsychopathological changes by organophosphorus compounds — a review

Human & Experimental Toxicology ◽

10.1177/096032719501401101 ◽

1995 ◽

Vol 14 (11) ◽

pp. 857-864 ◽

Cited By ~ 54

Author(s):

P. Eyer

Keyword(s):

Organophosphorus Compounds ◽

Toxic Effects ◽

Neuropathy Target Esterase ◽

Neurological Sequelae ◽

Visual Functions ◽

Organophosphate Intoxication ◽

Increasing Risk ◽

Clinically Significant ◽

High Doses

1 Available literature dealing with neuropsychopathologi cal changes after exposure to organophosphate insecti cides is reviewed. 2 Subacute neurological sequelae following acute organophosphate intoxication include the 'intermediate syndrome', probably a myopathy elicited by excess acetylcholine, and the 'organophosphate-induced delayed neuropathy' (OPIDN), which is caused by particularly neurotoxic organophosphates that inhibit neuropathy target esterase. 3 Long-term toxic effects affecting behaviour as well as mental and visual functions are occasionally observed after exposure to high doses of organophosphates with repeated acute, clinically significant intoxications. 4 The available data do not indicate that asymptomatic exposure to organophosphates is connected with an increasing risk of delayed or permanent neuro psychopathological effects.

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SWS/NTE-dependent neuropathy is the model system to study neurodegeneration

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v26.1243 ◽

2020 ◽

Vol 26 ◽

pp. 67-71

Author(s):

N. P. Matiytsiv

Keyword(s):

Life Expectancy ◽

Life Span ◽

Glial Cells ◽

Neurodegenerative Disorders ◽

Organophosphorus Compounds ◽

Transmembrane Protein ◽

Therapeutic Agents ◽

Model System ◽

Neuropathy Target Esterase ◽

Swiss Cheese

Today there is many described neurodegenerative D. melanogaster mutants, which characterized by development of degenerative changes in brain. One of them are a swiss cheese (sws) gene mutants. Mutations in this gene causes apoptosis of neurons and hyperwrapping of their somas by the glial cells, reducing of life expectancy and decrease of locomotion. The sws gene is the ortholog of mammal’s neuropathy target esterase (NTE / PNPLA6). NTE is s neuronal, transmembrane protein, that possesses serinesterase activity, and can be the target for neurotoxic organophosphorus compounds activity. Mutations in PNPLA6 gene cause number hereditary neurodegenerative disorders, which nowadays are incurable. The search for therapeutic agents require use of model objects because researches on humans have both methodical and ethical limitations. During two last decades D. melanogaster has proven itself as a good model for study of neurodegenerative diseases. In this review, we described general characteristics of D. melanogaster gene sws, consequences of its mutations and provided evidences of high conservatism of gene product. Keywords: gene swiss cheese, neuropathy target esterase, neurodegeneration, brain, life span.

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Acetylcholinesterase and Neuropathy Target Esterase Inhibitions in Neuroblastoma Cells to Distinguish Organophosphorus Compounds Causing Acute and Delayed Neurotoxicity,

Fundamental and Applied Toxicology ◽

10.1006/faat.1997.2330 ◽

1997 ◽

Vol 38 (1) ◽

pp. 55-63 ◽

Cited By ~ 70

Author(s):

M Ehrich

Keyword(s):

Organophosphorus Compounds ◽

Neuroblastoma Cells ◽

Neuropathy Target Esterase ◽

Delayed Neurotoxicity

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Biosensor assay of neuropathy target esterase in whole blood as a new approach to OPIDN risk assessment: review of progress

Human & Experimental Toxicology ◽

10.1177/0960327106070463 ◽

2007 ◽

Vol 26 (4) ◽

pp. 273-282 ◽

Cited By ~ 18

Author(s):

Galina F Makhaeva ◽

Vladimir V Malygin ◽

Nadezhda N Strakhova ◽

Larisa V Sigolaeva ◽

Lidia G Sokolovskaya ◽

...

Keyword(s):

Whole Blood ◽

Colorimetric Assay ◽

High Sensitivity ◽

Epidemiological Studies ◽

Neuropathy Target Esterase ◽

Carbon Paste ◽

New Approach ◽

Ongoing Work ◽

Hydrolysis Of ◽

Small Blood Volume

Organophosphates (OPs) that inhibit neuropathy target esterase (NTE) with subsequent ageing can produce OP-induced delayed neuropathy (OPIDN). NTE inhibition in lymphocytes can be used as a biomarker of exposure to neuropathic OPs. An electrochemical method was developed to assay NTE in whole blood. The high sensitivity of the tyrosinase carbon-paste biosensors for the phenol produced by hydrolysis of the substrate, phenyl valerate, allowed NTE activity to be measured in diluted samples of whole blood, which cannot be done using the standard colorimetric assay. The biosensor was used to establish correlations of NTE inhibitions in blood with that in lymphocytes and brain after dosing hens with a neuropathic OP. The results of further studies demonstrated that whole blood NTE is a reliable biomarker of neuropathic OPs for up to 96 hours after exposure. These validation results suggest that the biosensor NTE assay for whole blood could be developed to measure human exposure to neuropathic OPs as a predictor of OPIDN. The small blood volume required (100 μL), simplicity of sample preparation and rapid analysis times indicate that the biosensor should be useful in biomonitoring and epidemiological studies. The present paper is an overview of our previous and ongoing work in this area. Human & Experimental Toxicology (2007) 26, 273-282

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Changes of Neuropathy Target Esterase Affect Phospholipid Homeostasis in SK-N-SH Cells

Revista de Chimie ◽

10.37358/rc.20.8.8306 ◽

2020 ◽

Vol 71 (8) ◽

pp. 327-334

Author(s):

Li Yu-Yuan ◽

Wu Yi-Jun

Keyword(s):

In Vitro Model ◽

Organophosphorus Compounds ◽

Cell Model ◽

Neuropathy Target Esterase ◽

Phosphatidyl Glycerol ◽

In Vivo Experiments ◽

Vitro Model

Neuropathy target esterase (NTE), is a membrane protein located in the endoplasmic reticulum (ER). NTE has the activity of phospholipase B and can catalyze the deacylation of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to glycerylcholine (GPC). It is phosphorylated and aged by organophosphorus compounds (OPs), that induce delayed neuropathy in humans and sensitive animals. Our previous study has reported that the disruption of ER phospholipid homeostasis caused by the NTE inhibition may contribute to the initiation of the organophosphate-induced delayed neurotoxicity (OPIDN), while it is unknown how the disturbed phospholipid homeostasis initiates OPIDN. It is difficult to change phospholipids in in vivo experiments. Therefore, an in vitro model is urgently needed to explain the role of phospholipid homeostasis disorders in OPIDN. In this study, we altered the expression of NTE in SK-N-SH cells and determined its phospholipid component by using HPLC-MS. Our results showed that the changes of NTE affected the levels of PC, sphingomyelin (SM), phosphatidylethanolamine (PE), phosphatidylserine (PS), lysophosphatidylserine (LPS), phosphatidyl-glycerol (PG), and phosphatidylinositol (PI). Our results were consistent with the in vivo results. Furthermore, our findings indicate that the SK-N-SH cell model is a significantly useful method for the further research on how the changes of phospholipid homeostasis initiate the OPIDN, which is easier than the in vivo experiments in practice.

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