The neurotoxicant trimethyltin induces apoptosis via caspase activation, p38 protein kinase, and oxidative stress in PC12 cells.
Acute exposure to trimethyltin (TMT) causes neuronal degeneration in the hippocampus, amygdala, pyriform cortex, and neocortex [Am. J. Pathol. 97 (1979) 59]. Despite extensive efforts elucidating neuropathological changes and behavioral deficits following TMT exposure, only a limited amount of work has examined the molecular signaling mechanisms that lead to these changes. The present paper demonstrates that TMT impairs neurite outgrowth and cell viability in an in vitro model of neuronal development. The decrease in cell viability is paralleled by a decrease in cell body size, an increase in DNA fragmentation, activation of caspase-9, and cleavage of the caspase substrate poly-ADP ribose polymerase (PARP). These results suggest that TMT induces apoptosis. Pharmacological inhibition of caspase activity, p38 stress-responsive protein kinase activity, or oxidative stress prevented TMT-induced cell death. This work provides the first evidence for a TMT-initiated apoptotic pathway requiring oxidative stress, caspase activation, and p38 protein kinase activity.
Jenkins
Scott M
SM
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, OAQPS/ESD/REAG, C404-01, Research Triangle Park, NC 27711, USA. jemkins.scott@epa.gov
Barone
Stanley
S
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis*; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress; D016716:PC12 Cells / Q000187:drug effects* / Q000201:enzymology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D014298:Trimethyltin Compounds / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D014298:Trimethyltin Compounds; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C046488:trimethyltin; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases