| The dithiocarbamates are a group of compounds that are used extensively in industry, agriculture and medicine. Exposures to these compounds have caused deleterious effects to both the central and peripheral nervous systems. These dithiocarbamates are highly reactive substances that have strong chelating abilities and known sulfhydryl interactions. This project addresses the problem of neurotoxic injury to the cytoskeleton produced by exposure to the dithiocarbamates, specifically diethyldithio-carbamate (DDC). An in vitro cell culture model system has been used to investigate the toxic effects of DDC on the astroglial cytoskeleton.; Cultured rat hippocampal astroglia treated with 35 {dollar}mu{dollar}g/ml of DDC were studied for alterations to the cytoskeleton. Examination by both light microscopy and scanning electron microscopy revealed disruptions of the cytoskeleton occurring in a progressive time-dependent manner. The events initiating cytoskeletal injury appear to be related to DDC sulfhydryl interactions which preferentially target the cytoskeletal fraction. Lipid peroxidative injury occurred as a late secondary event with respect to cytoskeletal alterations. Copper was found to be closely associated with the cytoskeletal fraction. Electrophoretic patterns demonstrated two cytoskeletal protein alterations. The microtubular protein, {dollar}beta{dollar}-tubulin, appeared to have an altered mobility while the major intermediate filament protein, GFAP, was decreased. The addition of 10 mM glutathione to the media following DDC treatment appeared to stabilize the cytoskeletal architecture by preventing most of the morphologic changes.; The cytoskeleton appears to be an important cellular target for injury by DDC exposure. This research has demonstrated that DDC induces alterations in the architecture of the cytoskeleton of astroglia. These findings suggest that the DDC-induced alterations are related to copper accumulation, changes in microtubular and intermediate filament proteins, and an early preferential loss of cytoskeletal protein sulfhydryls. |
