A MECHANISTIC BIOASSAY FOR EPIGENETIC CARCINOGENS

描述：（改编自申请人的摘要）天然和合成 雌激素通常被认为是“内分泌干扰物”， 模仿或模仿激素正常活动的能力。虽然 内分泌干扰物的大多数良好表征的作用是受体介导的， 非受体介导的作用也可能在雌激素致癌作用中起作用 正如我们最近的研究所表明的，DES可以诱导异常的 在新的生物测定中报告转基因的超甲基化。基于 DNA甲基化的改变是一种驱动力， 体细胞和遗传性癌症的发展，这些数据提供了一个 强有力的理由，追求的机制，雌激素和其他 表观遗传致癌物可以改变DNA甲基化。表观基因检测是一种新的 哺乳动物细胞诱变试验，其利用一组独特的转基因 区分致突变性和表观遗传性的中国仓鼠细胞系 基因失活的机制该项目的短期目标是 评价DES、雌二醇和雌二醇改变DNA甲基化的能力。 儿茶酚雌激素代谢物和X射线（目的1）;以确定剂量 依赖性（目的2）和持久性（目的3）的任何改变DNA甲基化， 可能是由这些致癌物质引起的。在目标4中，将乳腺上皮细胞 用于筛选其表达可能被改变的表达下调的基因。 暴露于这些致癌物质后的DNA甲基化。的长期目标 本项目旨在进一步验证表观基因检测试剂盒用于常规 使用的实验和风险评估，以及机械研究， 改变DNA甲基化和基因表达。

DESCRIPTION: (Adapted from the applicant's abstract) Natural and synthetic estrogens are typically considered as "endocrine disruptors" by virtue of their ability to mimic or antagonixe the normal activity of hormone. Although the most well characterized effects of endocrine disruptors are receptor-mediated, non-receptor mediated effects may also be operative in estrogen carcinogenesis as suggested by our most recent demonstration that DES can induce aberrant hypermethylation of a reporter transgene in a novel bioassay. Based on the knowledge that altered DNA methylation is now known to be a driving force in the development of both somatic and inherited cancers, this data provide a strong rationale for pursuing the mechanism by which estrogens and other epigenetic carcinogens can alter DNA methylation. The Epigene assay is a novel mammalian cell mutagenesis assay that exploits a unique set of transgenic Chinese hamster cell lines to distinguish between mutagenic and epigenetic mechanisms of gene inactivation. The short term gola of this project are to evaluate the DNA methylation altering capacity of DES, estradiol, and a gew catechol estrogen metabolites, and X-rays (aim 1); to determine the dose dependence (aim 2) and permanence (aim 3) of any altered DNA methylation that may be induced by these carcinogens. In aim 4, mammary epithelial cells will be employed to screen for genes whose expression may be down regulated by altered DNA methylation following exposure to these carcinogens. The long term goals of this project are to further validate the use of the Epigene Assay for routine experimental and risk assessment used, as well as for mechanistic studies of altered DNA methylation and gene expression.