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Title: Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency

Abstract

Over the past several years evidence has been accumulating from in vivo animal studies, observations in humans, and in vitro studies, that organophosphorus (OP) insecticides may induce oxidative stress. Such effects may contribute to some of the toxic manifestations of OPs, particularly upon chronic or developmental exposures. The aim of this study was to investigate the role of oxidative stress in the neurotoxicity of two commonly used OPs, chlorpyrifos (CPF) and diazinon (DZ), their oxygen analogs (CPO and DZO), and their 'inactive' metabolites (TCP and IMP), in neuronal cells from a genetic model of glutathione deficiency. Cerebellar granule neurons from wild type mice (Gclm +/+) and mice lacking the modifier subunit of glutamate cysteine ligase (Gclm -/-), the first and limiting step in the synthesis of glutathione (GSH), were utilized. The latter display very low levels of GSH and are more susceptible to the toxicity of agents that increase oxidative stress. CPO and DZO were the most cytotoxic compounds, followed by CPF and DZ, while TCP and IMP displayed lower toxicity. Toxicity was significantly higher (10- to 25-fold) in neurons from Gclm (-/-) mice, and was antagonized by various antioxidants. Depletion of GSH from Gclm (+/+) neurons significantly increased theirmore » sensitivity to OP toxicity. OPs increased intracellular levels of reactive oxygen species and lipid peroxidation and in both cases the effects were greater in neurons from Gclm (-/-) mice. OPs did not alter intracellular levels of GSH, but significantly increased those of oxidized glutathione (GSSG). Cytotoxicity was not antagonized by cholinergic antagonists, but was decreased by the calcium chelator BAPTA-AM. These studies indicate that cytotoxicity of OPs involves generation of reactive oxygen species and is modulated by intracellular GSH, and suggest that it may involve disturbances in intracellular homeostasis of calcium.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [3]
  1. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105 (United States)
  2. Department of Human Anatomy, Pharmacology and Forensic Sciences, University of Parma Medical School (Italy)
  3. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105 (United States) and Department of Human Anatomy, Pharmacology and Forensic Sciences, University of Parma Medical School (Italy). E-mail: lgcosta@u.washington.edu
Publication Date:
OSTI Identifier:
20976883
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 219; Journal Issue: 2-3; Other Information: DOI: 10.1016/j.taap.2006.09.016; PII: S0041-008X(06)00347-4; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; CALCIUM; CYSTEINE; GLUTATHIONE; HOMEOSTASIS; HUMAN POPULATIONS; IN VITRO; IN VIVO; INSECTICIDES; LIGASES; LIPIDS; METABOLITES; MICE; NERVE CELLS; OXIDATION; SENSITIVITY; STRESSES; SYNTHESIS; TCP; TOXICITY

Citation Formats

Giordano, Gennaro, Afsharinejad, Zhara, Guizzetti, Marina, Vitalone, Annabella, Kavanagh, Terrance J., and Costa, Lucio G. Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.09.016.
Giordano, Gennaro, Afsharinejad, Zhara, Guizzetti, Marina, Vitalone, Annabella, Kavanagh, Terrance J., & Costa, Lucio G. Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency. United States. doi:10.1016/j.taap.2006.09.016.
Giordano, Gennaro, Afsharinejad, Zhara, Guizzetti, Marina, Vitalone, Annabella, Kavanagh, Terrance J., and Costa, Lucio G. Thu . "Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency". United States. doi:10.1016/j.taap.2006.09.016.
@article{osti_20976883,
title = {Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency},
author = {Giordano, Gennaro and Afsharinejad, Zhara and Guizzetti, Marina and Vitalone, Annabella and Kavanagh, Terrance J. and Costa, Lucio G.},
abstractNote = {Over the past several years evidence has been accumulating from in vivo animal studies, observations in humans, and in vitro studies, that organophosphorus (OP) insecticides may induce oxidative stress. Such effects may contribute to some of the toxic manifestations of OPs, particularly upon chronic or developmental exposures. The aim of this study was to investigate the role of oxidative stress in the neurotoxicity of two commonly used OPs, chlorpyrifos (CPF) and diazinon (DZ), their oxygen analogs (CPO and DZO), and their 'inactive' metabolites (TCP and IMP), in neuronal cells from a genetic model of glutathione deficiency. Cerebellar granule neurons from wild type mice (Gclm +/+) and mice lacking the modifier subunit of glutamate cysteine ligase (Gclm -/-), the first and limiting step in the synthesis of glutathione (GSH), were utilized. The latter display very low levels of GSH and are more susceptible to the toxicity of agents that increase oxidative stress. CPO and DZO were the most cytotoxic compounds, followed by CPF and DZ, while TCP and IMP displayed lower toxicity. Toxicity was significantly higher (10- to 25-fold) in neurons from Gclm (-/-) mice, and was antagonized by various antioxidants. Depletion of GSH from Gclm (+/+) neurons significantly increased their sensitivity to OP toxicity. OPs increased intracellular levels of reactive oxygen species and lipid peroxidation and in both cases the effects were greater in neurons from Gclm (-/-) mice. OPs did not alter intracellular levels of GSH, but significantly increased those of oxidized glutathione (GSSG). Cytotoxicity was not antagonized by cholinergic antagonists, but was decreased by the calcium chelator BAPTA-AM. These studies indicate that cytotoxicity of OPs involves generation of reactive oxygen species and is modulated by intracellular GSH, and suggest that it may involve disturbances in intracellular homeostasis of calcium.},
doi = {10.1016/j.taap.2006.09.016},
journal = {Toxicology and Applied Pharmacology},
number = 2-3,
volume = 219,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}