Neurotoxic and mutagenic actions of Superfund chemicals

有机氯溶剂是地下水、饮用水和饮用水供应的常见污染物，因此对人类健康构成特别重要的长期危害。在许多有机氯溶剂中，氯乙烯对人类的威胁最大，因为它非常普遍，是许多有机氯溶剂（如TCE、DCE）的常见代谢物，并初步与长期神经功能障碍和脑癌有关。鉴定生物标志物以确定与人类接触氯乙烯相关的相对健康风险是EPA的高度优先事项，也是本提案的长期目标。本研究的重点是确定氯乙烯的神经毒性和神经致癌机制，并将其作为风险评估的工具或生物标志物。氯乙烯单体的主要代谢物是氯乙醛（CAA），这是一种已知的人类和啮齿动物基因毒素，具有神经毒性、致突变性和致癌性。由于我们之前的工作表明，像CAA这样的烷基化剂（如甲基氧化甲醇，MAM）具有神经毒性，损伤DNA，干扰DNA修复，并且具有致突变性，因此我们提出CAA通过类似的机制诱导其神经毒性和致突变作用。提出了实验来检验乙基DNA加合物的形成与神经毒性或突变之间的关系。将从DNA修复熟练和缺陷小鼠（即k - n -甲基嘌呤DNA糖基酶Aag）的不同大脑区域（如皮层、海马、中脑、小脑）培养神经元和星形胶质细胞，并检查急性和延迟caa诱导的神经毒性。将从Aprt杂合缺陷小鼠中培养单独的星形胶质细胞，并检查以确定caa诱导突变的谱。这些研究结果有望为氯乙烯的神经毒性和致突变机制提供重要信息。

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.