Lymphocyte and brain neurotoxic esterase: Dose and time dependence of inhibition in the hen examined with three organophosphorus esters

Abstract

Certain organic phosphorus esters produce sensorimotor axonopathy in man and other species. There is an excellent correlation between the capacity of an organophosphorus compound to produce axonopathy and its ability to inhibit brain neurotoxic esterase (NTE) in hens. Because NTE is present in peripheral lymphocytes of both hen and man, it has been suggested that the lymphocyte enzyme might be useful both in experimental and clinical situations as an indicator of exposure to organophosphorus compounds producing axonopathy. Diethyl 4-nitrophenyl phosphate (paraoxon), tri-2-cresyl phosphate (TOCP), methyl 2,5-dichloro-4-bromophenyl phenylphosphonothionate (leptophos), and di-n-butyl-2,2-dichlorovinyl phosphate (di-n-butyl dichlorvos, DBDCV) were used to examine the relationship between lymphocyte and brain NTE inhibition in hens. As expected, paraoxon (0.75 mg/kg) did not inhibit NTE in brain or lymphocytes. TOCP (10 to 100 mg/kg), leptophos (25 to 150 mg/kg), and DBDCV (1.0 to 4.0 mg/kg) inhibited both brain and lymphocyte NTE activity in a dose-related manner with good correlation of inhibition between tissues taken 24 hr after exposure (r2 = 0.53 to 0.67; p less than 0.020 to 0.001). However, correlation of inhibition between tissues taken from animals killed 48 hr after exposures was poor (r2 = 0.15 to 0.30; p less than 0.10 to 0.05), with consistently less inhibition of lymphocyte NTE relative to brain NTE. This study indicates that assay of lymphocyte NTE can provide a good monitor of exposure to axonotoxic organophosphorus compounds within 24 hr between exposure and measurement.

Biosensor Detection of Neuropathy Target Esterase in Whole Blood as a Biomarker of Exposure to Neuropathic Organophosphorus Compounds

“…Inhibition of brain NTE within hours of exposure to a neuropathic OP compound predicts the potential for OPIDN to appear in susceptible animal models (e.g., adult hens) after a delay of 1 to 3 wk. NTE has also been found in circulating lymphocytes and platelets (Bertoncin etal., 1985;Dudek & Richardson, 1982;Maroni & Bleecker, 1986;Richardson & Dudek, 1983), and lymphocyte NTE has been used or proposed for use as an accessible biomarker of animal and human exposure to neuropathic OP compounds (Johnson, 1990;Lotti, 1986;Lotti et al, 1983Lotti et al, , 1986Richardson & Dudek, 1983;Schwab & Richardson, 1986). Furthermore, lymphocyte NTE inhibition has been suggested as a predictor of OPIDN or an adjunct for its early diagnosis (Ehrich, 1996;Lotti, 1987;Mutch et al, 1992;Richardson & Dudek, 1983;Wilson & Henderson, 1992).…”

“…Assay of lymphocyte NTE was shown to provide a reliable monitor of exposure to neuropathic OP compounds within 24h between exposure and measurement (Schwab & Richardson, 1986). To study the possibility of using blood NTE inhibition as a biochemical marker of neuropathic OP exposure and its correlation with brain NTE inhibition, two dosing experiments were carried out.…”

“…Lymphocyte NTE Lymphocytes were isolated as described (Schwab & Richardson, 1986) by centrifuging in a Ficoll-Verografin density gradient. The lymphocyte fraction was resuspended in working buffer to make a concentration equivalent to 2 × 10 7 to 4 × 10 7 cells/ml and sonicated (10 s, power output 50 W) before NTE assay by the colorimetric method of Johnson (1977) using a 40-min incubation with PV.…”

Neuropathy Target Esterase

“…Animal studies have been used to test correlations of inhibition in lymphocytes with that in brain (Makhaeva et al, 2003(Makhaeva et al, , 2007Richardson and Dudek, 1983;Richardson et al, 1993a,b;Schwab and Richardson, 1986). Lymphocyte NTE activity has been characterized in human populations (Bertoncin et al, 1985;Maroni and Bleecker, 1986) and used to monitor occupational exposures to potentially neuropathic OP compounds (Lotti et al, 1983(Lotti et al, , 1986McConnell et al, 1999).…”

Biomarker Research in Neurotoxicology: The Role of Mechanistic Studies to Bridge the Gap between the Laboratory and Epidemiological Investigations

“…A more detailed time-course study indicated a strong correlation between the levels of muscarinic receptors in brain areas and lymphocytes during the period of exposure (65 (81,82). Within 24 hr after acute exposure, there is a good correlation between lymphocyte and brain NTE in the hen, which is the species of choice for OPIDP studies (83). Measurement of lymphocyte NTE has been suggested as a potential biomarker to monitor for organophosphate-induced polyneuropathy (84).…”