Organochlorine solvents are a common contaminant of groundwater and drinking water and drinking water supplies and, therefore, pose a particularly important long-term health hazard to humans. Of the many organochlorine solvents, vinyl chloride poses the greatest threat to humans because it is highly prevalent, a common metabolite of many organochlorine solvents (e.g., TCE, DCE), and tentatively linked with long-term neurological dysfunction and brain cancer. The identification of biomarkers to determine the relative health risk associated with human exposure to vinyl chloride is a high priority of the EPA and a long-term objective of this proposal. The focus of the present study is to identify the neurotoxic and neuro-oncogenic mechanisms of vinyl chloride and to use these as tools or biomarkers for risk assessment. The major metabolite of vinyl chloride monomer (a Superfund chemical on the ATSDR priority list) is chloroacetaldehyde (CAA), a known human and rodent genotoxin with neurotoxic, mutagenic, and oncogenic properties. Because our previous work indicates that alkylating agents like CAA (e.g., methylazoxymethanol, MAM) are neurotoxic, damage DNA, perturb DNA repair, and are mutagenic, we propose that CAA induces its neurotoxic and mutagenic effects by a similar mechanism. Experiments are proposed to examine the relationship between the formation of etheno base DNA adducts and neurotoxicity or mutations. Neuronal and astrocyte cell cultures will be developed from different brain regions (e.g., cortex, hippocampus, midbrain, cerebellum) of DNA repair proficient and deficient mice (i.e.,k N-methylpurine DNA glycosylase Aag) and examined for acute and delayed CAA-induced neurotoxicity. Separate sets of astrocyte cell cultures will be developed from Aprt heterozygous- deficient mice and examined to determine the spectrum of CAA-induced mutations. Findings from these studies are expected to provide important information about the neurotoxic and mutagenic mechanisms of vinyl chloride.
Showing the most recent 10 out of 47 publications
