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

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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Studies on the delayed neurotoxicity of organophosphorus compounds. III.

The Journal of Toxicological Sciences ◽

10.2131/jts.10.67 ◽

1985 ◽

Vol 10 (2) ◽

pp. 67-82 ◽

Cited By ~ 10

Author(s):

Hirotoshi ITOH ◽

Hidemi KISHIDA ◽

Eiko TAKEUCHI ◽

Mamoru TADOKORO ◽

Toshiyuki UCHIKOSHI ◽

...

Keyword(s):

Organophosphorus Compounds ◽

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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Delayed Neurotoxicity of Organophosphorus Compounds

Journal of Enviromental Immunology and Toxicology ◽

10.7178/jeit.3 ◽

2013 ◽

Vol 1 (1) ◽

pp. 14 ◽

Cited By ~ 3

Author(s):

Kazim Husain ◽

Keyword(s):

Organophosphorus Compounds ◽

Delayed Neurotoxicity

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Characterization of [3H]di-isopropyl phosphorofluoridate-binding proteins in hen brain. Rates of phosphorylation and sensitivity to neurotoxic and non-neurotoxic organophosphorus compounds

Biochemical Journal ◽

10.1042/bj2280537 ◽

1985 ◽

Vol 228 (3) ◽

pp. 537-544 ◽

Cited By ~ 29

Author(s):

C D Carrington ◽

M B Abou-Donia

Keyword(s):

Organophosphorus Compound ◽

Binding Proteins ◽

Organophosphorus Compounds ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Reaction Rates ◽

Binding Activity ◽

Binding Characteristics ◽

Delayed Neurotoxicity ◽

Neurotoxic Esterase

The experiments described in this paper were designed to isolate [3H]di-isopropyl phosphorofluoridate-binding proteins by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis for the purpose of characterizing and identifying potential initiation sites for organophosphorus-compound-induced delayed neurotoxicity. The major Paraoxon-insensitive Mipafox-sensitive binding protein (Mr 160 000) was found to be identical with one previously identified as neurotoxic esterase, an enzyme that has been proposed to be the target site for organophosphorus-compound-induced delayed neurotoxicity. However, two other binding proteins with suitable binding characteristics were also found in smaller amounts, one of which has not been detected previously. Di-isopropyl phosphorofluoridate was found to phosphorylate all three of these proteins at rates similar to the rate at which neurotoxic esterase is inhibited by di-isopropyl phosphorofluoridate. Varying the concentration of di-isopropyl phosphorofluoridate or the time of incubation produced similar increases in binding to each of the labelled proteins. This suggests that the reaction rates of di-isopropyl phosphorofluoridate with proteins may be described by first-order kinetics, and the concentration of the Michael is complex formed during binding is minimal for all the phosphorylated proteins. The recovery of the binding activity in the 160 000-Mr band was found to be similar to the recovery of neurotoxic esterase activity, lending further support to the contention that this band is identical with neurotoxic esterase.

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Studies on the delayed neurotoxicity of organophosphorus compounds- (I)

The Journal of Toxicological Sciences ◽

10.2131/jts.6.287 ◽

1981 ◽

Vol 6 (4) ◽

pp. 287-300 ◽

Cited By ~ 1

Author(s):

Hirotoshi ITOH ◽

Mamoru TADOKORO ◽

Kiyoshi OIKAWA

Keyword(s):

Organophosphorus Compounds ◽

Delayed Neurotoxicity

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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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