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THE NEUROTOXICANT TRIMETHYLTIN STIMULATES APOPTOSIS VIA OXIDATIVE STRESS, CASPASE ACTIVATION AND P38 PROTEIN KINASE.
Citation:
Jenkins, S., L. D. White, AND S Barone. THE NEUROTOXICANT TRIMETHYLTIN STIMULATES APOPTOSIS VIA OXIDATIVE STRESS, CASPASE ACTIVATION AND P38 PROTEIN KINASE. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, UT, March 9-13, 2003.
Description:
Acute exposure to the tri-substituted organotin trimethyltin (TMT) causes neuronal degeneration in the hippocampus, amygdala, pyriform cortex, and neocortex. Developmental exposure to TMT impairs later learning and memory. Despite extensive efforts elucidating neuropathological changes and behavioral deficits following TMT exposure, little 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 differentiation utilizing NGF-primed PC12 cells. Similar doses of TMT were required for both of these effects suggesting that inhibition of neurite outgrowth might be a secondary consequence of decreased cell viability. The increase in cell death 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) suggesting that TMT induces apoptosis. Pharmacological inhibition of caspase activity, p38 stress-responsive protein kinase activity, or oxidative stress prevented TMT-induced cell death. Inhibition of JNK, another stress-responsive protein kinase, or PARP, a DNA repair enzyme thought to be involved in some forms of necrosis, did not prevent TMT-induced cell death. This work provides the first evidence for a TMT-initiated apoptotic pathway involving oxidative stress, caspase activation, and p38 activation. This abstract does not reflect EPA policy.