GENETIC AND REPRODUCTIVE TOXICITY OF ETHYLENE GLYCOL

乙二醇醚代表了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 吸入、皮肤和口服途径，因此， 家庭可能大量接触乙二醇醚。 低级烷烃 这一组的成员是高毒性的;特别是，2-甲氧基乙醇 （EGME），据报道，该物质可导致暴露人体的CNS毒性，以及 血液学和睾丸毒性。 EGME还导致 骨髓细胞染色体损伤和后代显性致死 暴露的小鼠和大鼠。 低剂量染毒后观察致突变作用 但大剂量后就不会了 多次低剂量给药后的遗传毒性效应 暴露，类似于人类暴露条件，还没有被 研究了 拟议的研究将检验两个假设：1）对于 高毒性试剂，如EGME，多次低剂量暴露更多 致突变性和毒性低于单次或多次高剂量; 2）EGME 原位代谢活化和结合是其靶点的原因 器官遗传毒性 具体目标是系统地评价 小鼠体细胞和雄性生殖细胞的细胞遗传学效应 单次低剂量暴露于宽剂量范围的EGME。 随后 将通过将小鼠暴露于 EGME的分次和多次给药（亚急性和亚慢性）。 将通过精母细胞试验评价遗传效应 并通过显性致死试验延长。 差异遗传毒性效应 将评估EGME在体细胞和雄性生殖细胞中的表达。 的 生殖细胞数据将用于估计群体中的遗传风险 暴露于EGME。 本研究旨在探讨EGME的毒性机制。 确定酶（醇和醛）的靶组织活性 脱氢酶），其将EGME转化为反应性代谢物。 潜在 将检测重复EGME暴露对这些酶的诱导。 标记的EGME将用于确定靶器官效应是否 与毒素的优先分布/结合相关。 这 这项研究将提供有关遗传学的重要信息。 EGME低剂量暴露的危害及靶器官损伤机制 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.