GENETIC AND REPRODUCTIVE TOXICITY OF ETHYLENE GLYCOL

乙二醇醚是一组在工业和工业中广泛使用的化学品 消费品。乙二醇醚很容易通过 因此，吸入、经皮和经口途径，人类职业和 家庭接触乙二醇醚的量可能很大。低碳烷烃 该族成员具有剧毒；特别是2-甲氧基乙醇 (卵子)，已被报道在暴露的人类中引起中枢神经系统毒性，以及 暴露动物的血液学和睾丸毒性。埃格姆还会导致 骨髓细胞染色体损伤与子代显性致死 暴露的小鼠和大鼠。观察低剂量组的诱变效果。 但不是在高剂量之后。小剂量多次给药的遗传毒性效应 类似于人类暴露条件的暴露，还没有 调查过了。拟议的研究将检验两个假设：1)对于 剧毒物质，如鸡蛋，多次低剂量暴露更多 具有诱变性，毒性低于单次或多次高剂量；2)鸡蛋 原位代谢激活和结合是其靶点 器官遗传毒性。具体目标是系统地评估 小鼠体细胞和雄性生殖细胞的细胞遗传学效应 单一低剂量暴露于大剂量范围的卵子。随后， 累积效应和剂量率效应将通过将小鼠暴露于 分次和多次剂量(亚急性和亚慢性)的卵子。 可传递的遗传效应将通过精母细胞检测进行评估。 并通过显性致死实验进行扩展。不同的遗传毒性效应 将评估卵子在体细胞和雄性生殖细胞中的含量。这个 生发细胞数据将用于估计人群中的遗传风险 暴露在蛋黄中。另一个目的是探讨鸡蛋毒性的机制。 测定酶(酒精和乙醛)的靶组织活性 脱氢酶)，将鸡蛋转化为反应性代谢物。潜力 通过反复接触鸡蛋来诱导这些酶的作用将被检测。 标记的鸡蛋将被用来确定靶器官效应是否 与毒素的优先分布/结合相关。这 拟议的研究将提供有关基因的重要信息 低剂量鸡蛋暴露的危害及其对靶器官的作用机制 遗传毒性。

Glycol ethers represent a group of widely used chemical in industry and in consumer products. Glycol ethers are readily absorbed through the inhalation, dermal and oral routes, therefore, human occupational and household exposure to glycol ethers can be substantial. The lower alkane members of this group are highly toxic; particularly, 2-methoxyethanol (EGME) which has been reported to cause CNS toxicity in exposed humans, and hematological and testicular toxicity in exposed animals. EGME also causes chromosome damage in bone marrow cells and dominant lethality in offspring of exposed mice and rats. The mutagenic effects were observed after low but not after high doses. Genotoxic effects after multiple low dose exposures, analogous to human exposure conditions, have not been investigated. Proposed research will examine two hypothesis: 1) that for highly toxic agents, like EGME, multiple low dose exposures are more mutagenic and less toxic than single or multiple high doses; 2) EGME metabolic activation in situ and binding are responsible for its target organ genotoxicity. Specific aims are to systematically evaluate the cytogenetic effect in somatic and in male germinal cells of mice after single low dose exposure to a wide dose range of EGME. Subsequently, the cumulative and dose-rate-effects will be analyzed by exposing mice to fractionated and multiple doses (subacute and subchronic) of EGME. Transmissible genetic effects will be evaluated by the spermatocyte assay and extended by the dominant lethal assay. Differential genotoxic effects of EGME in somatic and in male germinal cells will be evaluated. The germinal cell data will be used to estimate the genetic risk in population exposed to EGME. Anther aim is to probe the mechanism of EGME toxicity by determining target tissue activities of the enzymes (alcohol and aldehyde dehydrogenase) which convert EGME to reactive metabolites. Potential induction of these enzymes by repeated EGME exposure will be examined. Labeled EGME will be used to determine if target organ effects are associated with preferential distribution/binding of the toxin. This proposed study will provide important information regarding the genetic hazard from low dose exposure to EGME and the mechanism for target organ genotoxicity.