title: Mechanism of pyrethroid pesticide-induced apoptosis: role of calpain and the ER stress pathway.
abstract: Exposure to the pyrethroid pesticide deltamethrin has been demonstrated to cause apoptosis both in vitro and in vivo. However, the molecular pathways leading to deltamethrin-induced apoptosis have not been established. To identify these pathways, SK-N-AS neuroblastoma cells were exposed to deltamethrin (100 nM-5 μM) for 24-48 h. Deltamethrin produced a time- and dose-dependent increase (21-300%) in DNA fragmentation, an indicator of apoptosis. Data demonstrate that the initiation of DNA fragmentation resulted from interaction of deltamethrin with Na⁺ channels and consequent calcium influx, as tetrodotoxin and the intracellular Ca²⁺ chelator BAPTA-AM completely prevented apoptosis. DNA fragmentation was accompanied by increased caspase-9 and -3 activities and was abolished by specific caspase-9 and -3 inhibitors. However, deltamethrin did not increase cytosolic cytochrome c levels, indicating that the mitochondrial pathway was likely not involved. Additional studies demonstrated that deltamethrin exposure activated caspase-12 activity and that pharmacological inhibition and siRNA knockdown of calpain prevented deltamethrin-induced DNA fragmentation, thus indicating a role for the endoplasmic reticulum (ER) stress pathway. This was confirmed by the observation that inhibition of eIF2α abolished deltamethrin-induced DNA fragmentation. Together, these data demonstrate that deltamethrin causes apoptosis through its interaction with Na⁺ channels, leading to calcium overload and activation of the ER stress pathway. Because ER stress and the subsequent unfolded protein response have been observed in a number of neurodegenerative diseases, these data provide mechanistic information by which high-level exposure to pyrethroids may contribute to neurodegeneration.
authors.affiliation: Department of Environmental and Occupational Medicine and Environmental and Occupational Health Sciences Institute, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Hossain
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000494:pharmacology*; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009570:Nitriles / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D009570:Nitriles; D010575:Pesticides; D011722:Pyrethrins; D034741:RNA, Small Interfering; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C017180:decamethrin; D004533:Egtazic Acid; D045304:Cytochromes c; C506444:CASP12 protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D002154:Calpain; D053454:Caspase 12; D053148:Caspase 3; D053453:Caspase 9; D002118:Calcium