MOLECULAR TOXICOLOGY OF ORGANOTIN COMPOUNDS

Project: Research project

Project Details

Description

Mechanisms of selective neurotoxicants remains a key issue in neurotoxicology. We propose to use molecular biologic approaches to address specific mechanisms which may explain the selective actions of organotin toxicants. Organotins cause neuronal and immune cell apoptosis in vitro, and this is mediated in part by stannin, a protein which was isolated via subtractive hybridization from organotin-sensitive tissues. In specific aim I, we will investigate the normal function of stannin, and will use targeted gene disruptions to determine the consequences of loss of stannin on the elaboration of organotin toxicity. If stannin is necessary for selective toxicant action, reductions in this protein should blunt neurotoxicity and immunotoxicity. We have characterized murine genomic clones, and are producing a targeting vector for disruption of the stannin open reading frame. Results suggest that stannin is highly conserved between species; the predicted amino acid sequence is identical between mice and rats, with only 8 conservative substitutions at the nucleotide level in the cDNA. The second aim will use in vivo antisense disruption of stannin expression in vivo to determine whether this protein is needed for the elaboration of organotin toxicity. We hypothesize that reductions in stannin protein levels will blunt the toxicity of TMT. The third aim will focus on whether stannin acts to promote cellular apoptosis. Initial studies have shown that organotin compounds induce an apoptotic cell death in a stannin-dependent manner. We will extend these findings and will determine whether stannin acts as a direct mediator of apoptosis or acts via interactions with other known signaling mechanisms of apoptosis. This aim will also use yeast two-hybrid systems and stannin affinity matrices to determine protein-protein interactions with stannin. Together, these aims will extend and expand our initial studies of selective toxicants, and may lead to the development of new approaches for mechanistic analysis of toxicity.
StatusFinished
Effective start/end date9/17/906/30/03

Funding

  • National Institute of Environmental Health Sciences: $171,854.00

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