TUMOR INDUCTION BY ACRYLONITRILE AND ITS EPOXIDE

丙烯腈(AN)在工业中广泛使用，具有潜在的接触 给成千上万的工人。它对人类的潜在危险一直是 获得OSHA认可。AN是大鼠体内的致癌物，其独特之处在于 在成年大鼠体内产生脑瘤的能力。在…的基础上 其他人的新陈代谢研究，以及AN与乙烯的结构相似性 据推测，一种新陈代谢激活的形式的AN， 环氧丙烯腈(ANE)可能是AN的最终致癌形式。 在过去的授权期内，我们已经直接证明了 在体外通过Michael加成反应使小牛胸腺DNA中的所有碱基烷化 生理pH和温度。氰乙基加合物用 鸟嘌呤、胸腺嘧啶和羧乙基加合物与腺嘌呤和 胞嘧啶。羧乙基加合物与生成的加合物相同。 来自另一种啮齿动物致癌物质的体外反应， β-丙内酯，与小牛胸腺DNA。也观察到了类似的发现 当工业上重要的和结构相关的化合物 丙烯酰胺(AM)和丙烯酸(AA)与 2‘-脱氧核苷。拟议工作的主要目标是 确定体内与DNA形成的加合物的性质，即 和/或加合物。因此，加合物的结构将被确定 雌性SD大鼠脑DNA(靶组织DNA)、星形胶质细胞 组织培养和小鼠成纤维细胞C3H/10T1/2中的靶细胞DNA [2，3-C14]AN暴露后组织培养中克隆8细胞DNA。在……里面 在老鼠的情况下，暴露会被水摄取。其他 目标是确定形成的加合物的结构 AM、AA和环氧化丙烯酰胺(AME)与 小牛胸腺DNA用于其体内反应的未来可能研究 DNAANE和AME将用于对 雌性ICR/Ha小鼠背部皮肤。此外，肿瘤性转化 使用AN、ANE、AM和AME的研究将使用星形胶质细胞(来自 新生SD大鼠脑)和C3H/10T1/2细胞进行组织培养。

Acrylonitrile (AN) is used extensively in industry with potential exposure to hundreds of thousands of workers. Its potential danger to man has been recognized by OSHA. AN is a carcinogen in the rat and is unique in its ability to produce brain tumors in the adult rat. On the basis of metabolism studies, by others, and the structural similarity of AN to vinyl chloride it has been postulated that a metabolically activated form of AN, acrylonitrile epoxide (ANE) may be the ultimate carcinogenic form of AN. During the past grant period we have demonstrated that AN directly alkylates all bases in calf thymus DNA (in vitro) by Michael addition at physiological pH and temperature. Cyanoethyl-adducts were isolated with guanine and thymine and carboxyethyl-adducts resulted with adenine and cytosine. The carboxyethyl-adducts were identical to adducts resulting from the in vitro reaction of another rodent carcinogen, beta-propiolactone, with calf thymus DNA. Similar findings were observed when the industrially important and structurally related compounds acrylamide (AM) and acrylic acid (AA) were reacted with 2'-deoxy-nucleosides. The major objective of the proposed work is to determine the nature of the adducts formed with DNA in vivo, i.e., AN and/or ANE adducts. Thus, the structures of the adducts will be determined in female Sprague Dawley rat brain DNA (target tissue DNA), astrocyte cell DNA (target cell DNA) in tissue culture and mouse fibroblast C3H/10T1/2 clone 8 cell DNA in tissue culture following exposure to [2,3-C14]AN. In the case of the rats, exposure will be by water ingestion. Other objectives are the determination of the structure of adducts formed following in vitro reaction of AM, AA and acrylamide epoxide (AME) with calf thymus DNA for possible future studies on their in vivo reactions with DNA. ANE and AME will be used in complete carcinogenicity studies on the dorsal skins of female ICR/Ha mice. In addition, neoplastic transformation studies using AN, ANE, AM and AME will be conducted using astrocytes (from neonatal Sprague Dawley rat brains) and C3H/10T1/2 cells in tissue culture.