Reduced cellular redox status induces 4-hydroxynonenal-mediated caspase 3 activation leading to erythrocyte death during chronic arsenic exposure in rats

• Published in: Toxicology and applied pharmacology Vol. 244; no. 3; pp. 315 - 327
• Main Authors: Biswas, Debabrata, Sen, Gargi, Biswas, Tuli
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-05-2010; Elsevier
• Subjects: 4-Hydroxynonenal; 60 APPLIED LIFE SCIENCES; ALDEHYDES; Aldehydes - metabolism; Anemia - chemically induced; Anemia - enzymology; Anemia - metabolism; ANIMALS; ANTIOXIDANTS; ARSENIC; Arsenic - metabolism; Arsenic - toxicity; Arsenic exposure; Biological and medical sciences; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY FLUIDS; Carcinogenesis, carcinogens and anticarcinogens; Caspase 3; Caspase 3 - metabolism; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; CHEMICAL REACTIONS; CHRONIC EXPOSURE; DEATH; ELEMENTS; Environmental Pollutants - metabolism; Environmental Pollutants - toxicity; Enzyme Activation - drug effects; Erythrocyte; ERYTHROCYTES; Erythrocytes - drug effects; Erythrocytes - enzymology; Erythrocytes - metabolism; HNE; HYDROGEN COMPOUNDS; HYDROGEN PEROXIDE; Hydrogen Peroxide - metabolism; Hydroxyl Radical - metabolism; HYDROXYL RADICALS; LIFE SPAN; Male; MAMMALS; MATERIALS; Medical sciences; MEMBRANE PROTEINS; Metals and various inorganic compounds; ORGANIC COMPOUNDS; OXIDATION; Oxidation-Reduction - drug effects; Oxidative stress; Oxidative Stress - drug effects; OXYGEN COMPOUNDS; PEROXIDES; PROTEINS; RADICALS; RATS; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; RODENTS; ROS; SEMIMETALS; STRESSES; Superoxides - metabolism; TOXICITY; Toxicity Tests, Chronic; Toxicology; Tumors; VERTEBRATES; Erythrocyte; Caspase 3; Oxidative stress; Arsenic exposure; HNE; ROS; Arsenic; Rat; Cysteine endopeptidases; Redox state; Enzyme; Mortality; Rodentia; Red blood cell; Exposure; In vitro; Peptidases; Carcinogen; Blood cell; Vertebrata; Chronic; Mammalia; Animal; Hydrolases; Death
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2010.01.009

Chronic exposure to arsenic in rats led to gradual accumulation of the toxicant in erythrocytes causing oxidative stress in these cells. 4-Hydroxynonenal (4-HNE), a major aldehyde product of lipid peroxidation, contributed significantly to the cytopathological events observed during oxidative stress in the erythrocytes of exposed rats. 4-HNE triggered death signal cascade that was initiated with the formation of HNE–protein adducts in cytosol. HNE–protein adduct formation resulted in depletion of cytosolic antioxidants followed by increased generation of ROS. Results showed accumulation of hydrogen peroxide (H
2O
2) from the early stages of arsenic exposure, while superoxide (O
2
•−) and hydroxyl radical (
•OH) also contributed to the oxidative stress during longer period of exposure. Suppression of antioxidant system coupled with increased generation of ROS eventually led to activation of caspase 3 during arsenic exposure. Attenuation of HNE-mediated activation of caspase 3 in presence of
N-acetylcysteine (NAC) indicated the involvement of GSH in the process. Prevention of HNE-mediated degradation of membrane proteins in presence of Z-DEVD-FMK identified caspase 3 as the principal mediator of HNE-induced cellular damage during arsenic exposure. Degradation of band 3 followed by its aggregation on the red cell surface promoted immunologic recognition of redistributed band 3 by autologous IgG with subsequent attachment of C3b. Finally, the formation of C3b–IgG–band 3 immune complex accelerated the elimination of affected cells from circulation and led to the decline of erythrocyte life span during chronic arsenic toxicity.