title: Phorate-induced oxidative stress, DNA damage and transcriptional activation of p53 and caspase genes in male Wistar rats.
abstract: Male Wistar rats exposed to a systemic organophosphorus insecticide, phorate [O,O-diethyl S-[(ethylthio) methyl] phosphorothioate] at varying oral doses of 0.046, 0.092 or 0.184mg phorate/kg bw for 14days, exhibited substantial oxidative stress, cellular DNA damage and activation of apoptosis-related p53, caspase 3 and 9 genes. The histopathological changes including the pyknotic nuclei, inflammatory leukocyte infiltrations, renal necrosis, and cardiac myofiber degeneration were observed in the liver, kidney and heart tissues. Biochemical analysis of catalase and glutathione revealed significantly lesser activities of antioxidative enzymes and lipid peroxidation in tissues of phorate exposed rats. Furthermore, generation of intracellular reactive oxygen species and reduced mitochondrial membrane potential in bone marrow cells confirmed phorate-induced oxidative stress. Significant DNA damage was measured through comet assay in terms of the Olive tail moment in bone marrow cells of treated animals as compared to control. Cell cycle analysis also demonstrated the G(2)/M arrest and appearance of a distinctive SubG(1) peak, which signified induction of apoptosis. Up-regulation of tumor suppressor p53 and caspase 3 and 9 genes, determined by quantitative real-time PCR and enzyme-linked immunosorbent assay, elucidated the activation of intrinsic apoptotic pathways in response to cellular stress. Overall, the results suggest that phorate induces genetic alterations and cellular toxicity, which can adversely affect the normal cellular functioning in rats.
authors.affiliation: Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Quaiser
authors.initials: Q
authors.lastname: Saquib
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
authors.forename: Maqsood A
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: Mourad A M
authors.initials: MA
authors.lastname: Aboul-Soud
authors.forename: Abdulaziz A
authors.initials: AA
authors.lastname: Al-Khedhairy
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.forename: Javed
authors.initials: J
authors.lastname: Musarrat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics; D053453:Caspase 9 / Q000235:genetics; D020169:Caspases / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007306:Insecticides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010702:Phorate / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D007306:Insecticides; D016159:Tumor Suppressor Protein p53; D010702:Phorate; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases