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STRUCTURE-ACTIVITY RELATIONSHIP AMONG ORGANOTINS IN AN IN VITRO MODEL OF NEURONAL DIFFERENTIATION AND PROGRAMMED CELL DEATH.
Citation:
Jenkins, S., L. D. White, AND S Barone. STRUCTURE-ACTIVITY RELATIONSHIP AMONG ORGANOTINS IN AN IN VITRO MODEL OF NEURONAL DIFFERENTIATION AND PROGRAMMED CELL DEATH. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, UT, March 9-13, 2003.
Description:
The organotins are used as heat stabilizers in PVC pipes and as marine biocides. Human exposure to monomethyltin (MMT) and dimethyltin (DMT) can occur in the water supply as a result of leaching from PVC pipes. Developmental exposure of rats to MMT and the known neurotoxicant trimethyltin (TMT) results in neurobehavioral impairments. Here we compared the effects of MMT, DMT, and TMT on neurite outgrowth and cell viability, endpoints relevant for developmental neurotoxicity, using rat pheochromocytoma (PC12) cells. The dose-response curve for the effects of TMT on neurite outgrowth was steep with 2 mM TMT having no significant effect while 4.0 mM TMT inhibited NGF-induced neurite outgrowth by approximately 80%. Higher concentrations of TMT further inhibited neurite outgrowth. Dimethyltin also inhibited neurite outgrowth at low micromolar concentrations although not as dramatically. NGF-stimulated neurite outgrowth was inhibited by approximately 6% in the presence of 2.0 mM DMT. Higher concentrations of DMT resulted in progressively greater inhibition of neurite outgrowth. MMT did not have any significant effects on NGF-stimulated neurite outgrowth. Cell viability following organotin treatment was measured by trypan blue exclusion. Treatment with 6.0 mM TMT increased the percentage of non-viable cells from 7% to 16%. Treatment with 10 mM DMT increased the percentage of non-viable cells to approximately 18%. Higher concentrations of DMT caused a further increase in the percentage of non-viable cells. MMT had no significant effect on cell viability at any concentration tested. The cell death induced by TMT was apoptotic as indicated by increased DNA fragmentation while that induced by DMT was not. Our results will be correlated with neurotoxic effects observed following organotin administration in vivo to determine whether this type of in vitro assay can be used as a predictor of in vivo toxicity when evaluating a family of compounds. Because human exposure to MMT and DMT occurs as a mixture, we will also evaluate the effect of MMT and DMT mixtures on neurite outgrowth and cell viability. This abstract does not reflect EPA policy.