Enantiomer-specific profenofos-induced cytotoxicity and DNA damage mediated by oxidative stress in rat adrenal pheochromocytoma (PC12) cells

• Published in: Journal of applied toxicology Vol. 34; no. 2; pp. 166 - 175
• Main Authors: Lu, Xianting, Yu, Cheng
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2014; Wiley Subscription Services, Inc
• Subjects: Adrenal glands; Animals; Antioxidants - pharmacology; Catalase - genetics; Catalase - metabolism; Cell Survival - drug effects; Comet Assay; Cytotoxicity; Damage; Deoxyribonucleic acid; DNA damage; DNA Damage - drug effects; enantioselectivity; Gene expression; Genotoxicity; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Malondialdehyde; Malondialdehyde - metabolism; Organothiophosphates - toxicity; Oxidative stress; Oxidative Stress - drug effects; PC12 Cells; Pesticides - toxicity; profenofos; Rats; Reactive Oxygen Species - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Stereoisomerism; Stresses; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Toxicity; Viability; Vitamin E - pharmacology; enantioselectivity; profenofos; DNA damage; cytotoxicity; oxidative stress
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.2847

ABSTRACT Recent studies have shown that chiral pesticides could enantioselectively induce cytotoxicity and genotoxicity. However, investigations on molecular mechanisms of enantioselective toxicity of pesticides are limited. In this study, the role of oxidative stress in enantiomer‐specific, profenofos (PFF)‐induced cytotoxicity and genotoxicity was investigated using PC12 cells. The results demonstrated that PFF enantioselectively reduced cell viability and induced DNA damage in PC12 cells. A concentration‐ and time‐dependent significant induction of reactive oxygen species (ROS), malondialdehyde and gene expression encoding antioxidant enzyme (Cu‐ZnSOD, GST and CAT) and stress protein (HSP 70 and HSP 90) was observed in (−)­PFF, whereas (+)­PFF and rac‐PFF exhibited these effects to lesser degrees. Pre‐treatment with vitamin E (600 μM) caused a significant attenuation in the toxic effect; reversing subsequent PFF‐induced elevation of ROS and malondialdehyde (MDA) levels, further strengthening the involvement of oxidative stress in PFF‐mediated toxicity. In addition, the results also showed that PFF‐dependent ROS accumulation, MDA release and oxidative stress gene expression preceded the loss of cell viability and induction of DNA damage, and already significantly changed at concentrations which are not yet cytotoxic or genotoxic. These results indicate that oxidative stress may contribute to PFF‐induced toxicity and that it was not a consequence of it. Copyright © 2013 John Wiley & Sons, Ltd. This study investigated the role of oxidative stress in enantiomer‐specific, profenofos (PFF)‐induced cytotoxicity and genotoxicity in PC12 cells. A concentration‐ and time‐dependent significant reduction of cell viability and induction of DNA damage, reactive oxygen species, malondialdehyde and gene expression was observed in (−)PFF, while (+)PFF and rac‐PFF exhibited these effects to lesser degrees. Pre‐treatment with vitamin E (600 μM) caused a significant attenuation in the toxic effect, further strengthening the involvement of oxidative stress in PFF mediated toxicity.