TUMOR INDUCTION BY ACRYLONITRILE AND ITS EPOXIDE

丙烯腈（AN）在工业中广泛使用，具有潜在的暴露风险 to hundreds十of thousands数千of workers工人. 它对人类的潜在危险 得到OSHA的认可。 AN在大鼠中是一种致癌物质， 在成年大鼠中产生脑肿瘤的能力。 的基础上 其他人的代谢研究以及AN与乙烯基的结构相似性 氯化物已经假定AN的代谢活化形式， 环氧化丙烯腈（ANE）可能是AN的最终致癌形式。 在过去的赠款期间，我们已经证明，AN直接 通过Michael加成使小牛胸腺DNA（体外）中的所有碱基烷基化， 生理pH和温度。 氰乙基-加合物分离与 鸟嘌呤和胸腺嘧啶和羧乙基加合物与腺嘌呤和 胞嘧啶 羧乙基加合物与得到的加合物相同。 另一种啮齿动物致癌物的体外反应， β-丙内酯，小牛胸腺DNA。 观察到类似的发现 当工业上重要的和结构上相关的化合物 丙烯酰胺（AM）和丙烯酸（AA）反应， 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，一个 和/或ANE加合物。 因此，将确定加合物的结构 在雌性Sprague道利大鼠脑DNA（靶组织DNA）中，星形胶质细胞 组织培养物和小鼠成纤维细胞C3 H/10 T1/2中的DNA（靶细胞DNA） 在暴露于[2，3-C14]AN之后，在组织培养物中克隆8细胞DNA。 在 对于大鼠，将通过饮水进行暴露。 其他 目的是确定形成的加合物的结构 在AM、AA和丙烯酰胺环氧化物（AME）与 小牛胸腺DNA，用于将来可能研究其与 DNA. ANE和AME将用于对以下物质的完整致癌性研究： 雌性ICR/Ha小鼠的背部皮肤。 此外，肿瘤转化 使用AN、ANE、AM和AME的研究将使用星形胶质细胞（来自 新生Sprague道利大鼠脑）和组织培养物中的C3 H/10 T1/2细胞。

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.