TY - JOUR
T1 - Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine
AU - Peña-Llopis, Samuel
AU - Ferrando, M. Dolores
AU - Peña, Juan B.
N1 - Funding Information:
This work was supported by the CICYT-FEDER Grant 1FD1997-0943-CO2-02. Samuel Peña-Llopis was recipient of a research grant from the Spanish Council for Scientific Research (CSIC). The authors thank Germán Cañavate for his help in checking fish mortality and performing some biochemical determinations; Dr. Guido van den Thillart and Richard van Heeswijk for providing the Multiskan Ascent microplate reader; and Dr. Carlos Saavedra for reviewing the manuscript. The fish farm Valenciana de Acuicultura S.A. is also greatly acknowledged for kindly providing European eels.
PY - 2003/12/10
Y1 - 2003/12/10
N2 - Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1mmolkg -1, i.p.) and exposed to 1.5mgl-1 (the 96-h LC 85) of dichlorvos for 96h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and γ-glutamyl transferase (γGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.
AB - Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1mmolkg -1, i.p.) and exposed to 1.5mgl-1 (the 96-h LC 85) of dichlorvos for 96h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and γ-glutamyl transferase (γGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.
KW - Biomarkers
KW - Dichlorvos
KW - Glutathione redox status
KW - Necrosis
KW - Organophosphorus pesticide
KW - Tolerance
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U2 - 10.1016/S0166-445X(03)00148-6
DO - 10.1016/S0166-445X(03)00148-6
M3 - Article
C2 - 14568351
AN - SCOPUS:0142042895
SN - 0166-445X
VL - 65
SP - 337
EP - 360
JO - Aquatic Toxicology
JF - Aquatic Toxicology
IS - 4
ER -