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。在众多有机氯溶剂中，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。确定生物标记物以确定与人类接触氯乙烯相关的相对健康风险是环境保护局的高度优先事项，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，并将其用作风险评估的工具或生物标记物。氯乙烯单体(ATSDR优先名单上的超级基金化学品)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遗传毒素，具有神经毒性、突变和致癌特性。由于我们以前的工作表明，像CAA这样的烷基化试剂(如甲氧基甲醇，MAM)具有神经毒性、损伤DNA、扰乱DNA修复和致突变作用，因此我们认为CAA通过类似的机制诱导其神经毒性和突变作用。建议进行实验，以检查亚乙基DNA加合物的形成与神经毒性或突变之间的关系。神经细胞和星形胶质细胞将从DNA修复熟练和缺陷小鼠的不同脑区(如皮质、海马体、中脑、小脑)培养出来(即k N-甲基嘌呤DNA糖基化酶AAG)，并检测急性和延迟CAA诱导的神经毒性。将从APRT杂合子缺陷小鼠中分离培养星形胶质细胞，并对其进行检查，以确定CAA诱导的突变谱。这些研究的结果有望为氯乙烯的神经毒性和诱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.