title: The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human Pulmonary Cells.
abstract: Organophosphorus (OP) pesticides are known to induce pulmonary toxicity in both humans and experimental animals. To elucidate the mechanism of OP-induced cytotoxicity, we examined the effects of parathion and malathion and their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells. Exposure to paraoxon and malaoxon produced a dose-dependent increase in cytotoxicity following a 24-hour exposure, while treatment with parathion or malathion produced no effects at clinically relevant concentrations. Exposure to paraoxon-induced caspase activation, but malaoxon failed to induce this response. Since caspases have a major role in the regulation of apoptosis and cell death, we evaluated OP-induced cell death in the presence of a caspase inhibitor. Pharmacological caspase inhibition protected against paraoxon-induced cell death but not malaoxon-induced cell death. These data suggest that caspase activation is a key signaling element in paraoxon-induced cell death, but not malaoxon-induced cellular death in the pulmonary epithelium.
authors.affiliation: National Research Council, Research Associates Program, Washington DC, USA Excet Inc, Springfield, VA, USA daniel.j.angelini2.ctr@mail.mil.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Angelini
authors.affiliation: Chemical & Biological Technologies Department, Defense Threat Reduction Agency, Fort Belvoir, VA, USA Battelle Memorial Institute, Columbus, OH, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Moyer
authors.affiliation: National Research Council, Research Associates Program, Washington DC, USA Excet Inc, Springfield, VA, USA Chemical & Biological Technologies Department, Defense Threat Reduction Agency, Fort Belvoir, VA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cole
authors.affiliation: National Research Council, Research Associates Program, Washington DC, USA Chemical & Biological Technologies Department, Defense Threat Reduction Agency, Fort Belvoir, VA, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Willis
authors.affiliation: U.S. Army Medical Command, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, MD, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Oyler
authors.affiliation: U.S. Army Research Development and Engineering Command, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA.
authors.forename: Russell M
authors.initials: RM
authors.lastname: Dorsey
authors.affiliation: U.S. Army Research Development and Engineering Command, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA Department of Homeland Security, Chemical Security Assessment Center, Aberdeen Proving Ground, MD, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Salem
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D008294:Malathion / Q000031:analogs & derivatives* / Q000633:toxicity; D010261:Paraoxon / Q000633:toxicity*; D010278:Parathion / Q000633:toxicity; D012137:Respiratory System / Q000166:cytology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D002800:Cholinesterase Inhibitors; D007306:Insecticides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C100082:malaoxon; D010278:Parathion; D020169:Caspases; D010261:Paraoxon; D008294:Malathion
keywords: apoptosis; caspase; malaoxon; necrosis; organophosphates; paraoxon; pulmonary toxicity