EPIGENETIC MECHANISMS AS FETAL BASIS OF TRANSPLACENTAL ARSENIC CARCINOGENISIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 砷是已知的人类致癌物质，但在成年动物身上很难产生肿瘤。 在生物检测中独树一帜。我们建立了一种经胎盘砷致癌的动物模型。在这 模型组小鼠于妊娠第8~18天通过饮用无机砷灌胃。 后代在成年后患上了肝脏肿瘤和其他部位的肿瘤。的确，胎盘或早产儿 接触无机砷会导致人类患上一系列肿瘤和其他疾病。的基础 砷致癌的“发育起源”范式没有得到充分的定义，并在体内积累 有证据表明，这是表观遗传学的基础。这项试点拨款提案的目标是利用全基因组 阐明砷诱导的早期生命重编程调控机制的方法。我们的 中心假说是子宫内砷暴露对发育可塑性的反应是连续的 受表观遗传机制调控的事件，这将是肿瘤基因重新编程的关键 在生命的后期发展。目标1将确定子宫内砷引起的DNA变化 甲基化。抗5-甲基胞嘧啶的单抗将用于进行显色免疫沉淀 (芯片)结合下一代测序确定全基因组 子宫内砷暴露引起的甲基化改变。目标2将确定宫内砷中毒 MicroRNAs的表达变化及其与3‘-UTR基因的结合。建议数 这项研究是新颖的，因为它将使用全基因组的方法来阐明无机砷如何暴露在 子宫在发育过程中调节表观遗传机制。这项拟议的研究意义重大，因为 关于体内早期接触砷致癌的表观遗传调控知之甚少。这个 成功完成砷诱导的胎儿表观遗传学改变将产生关键知识 导致美国国立卫生研究院申请深入研究胎儿经胎盘砷的基础 致癌。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Arsenic is a known human carcinogen, but it has been difficult to produce tumors in adult animals by arsenic alone in bioassays. We have developed an animal model of transplacental arsenic carcinogenesis. In this model, pregnant mice was given inorganic arsenic through the drinking water from gestation day 8 to 18, and the offspring developed liver tumors and tumors in other sites in adulthood. Indeed, transplacental or earlylife exposure to inorganic arsenic induces a spectrum of tumors and other diseases in humans. The basis of the "developmental origins" paradigm of arsenic carcinogenesis is not fully defined, and accumulating evidence suggests an epigenetic basis. The objective of this pilot grant proposal is to utilize genome-wide approaches to elucidate the regulatory mechanisms of arsenic-induced early-life reprogramming. Our central hypothesis is that developmental plasticity responding to in utero arsenic exposure is a sequential event regulated by epigenetic mechanisms, which would be critical for genetic reprogramming for tumor development much later in life. Aim 1 will determine the in utero arsenic-induced changes in DNA methylation. The monoclonal antibody against 5-methylated cytosine will be used to perform chromatinimmunoprecipitation (ChiP) coupled with the Next-Generation Sequencing to determine the genome-wide methylation alterations as a result of in utero arsenic exposure. Aim 2 will determine the in utero arsenicinduced expression changes in microRNAs and their binding to 3'-UTR genes of interest. The proposed study is novel, because it will use a genome-wide approach to elucidate how inorganic arsenic exposure in utero regulates epigenetic machinery during development. The proposed study is significant, because very little is known about epigenetic regulation of arsenic carcinogenesis during early-life exposure in vivo. The successful completion of arsenic-induced epigenetic changes in the fetus will generate critical knowledge leading to a NIH grant application to go into depth to elucidate the fetal basis of transplacental arsenic carcinogenesis.