A MECHANISTIC BIOASSAY FOR EPIGENETIC CARCINOGENS

描述：(改编自申请人的摘要)天然的和合成的 雌激素通常被认为是“内分泌干扰物”，因为它们 模拟或对抗荷尔蒙正常活动的能力。尽管 内分泌干扰物最典型的作用是受体介导的， 非受体介导的效应也可能在雌激素致癌中起作用。 正如我们最新的证明所表明的，DES可以诱导异常 在一种新的生物检测中报告转基因的高甲基化。基于 现在已知改变的DNA甲基化是一种驱动力 躯体和遗传性癌症的发展，这一数据提供了一个 追求雌激素和其他物质 表观致癌物质可以改变DNA甲基化。表观分析是一种新颖的方法。 利用一套独特的转基因技术进行哺乳动物细胞诱变试验 中国仓鼠细胞系区分诱变和表观遗传 基因失活的机制。这个项目的短期目标是 评估DES、雌二醇和GEW的DNA甲基化改变能力 儿茶酚、雌激素代谢物和X光(目标1)；确定剂量 依赖(目标2)和永久性(目标3)任何改变的DNA甲基化 可能是由这些致癌物引起的。在目标4中，乳腺上皮细胞将被 用于筛选其表达可能被改变下调的基因 接触这些致癌物后的DNA甲基化。的长期目标 本项目旨在进一步验证表观化学检测在常规检测中的应用 用于实验和风险评估，以及用于机械研究 改变了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.