EPIGENETIC MECHANISMS AS FETAL BASIS OF TRANSPLACENTAL ARSENIC CARCINOGENISIS

作为经胎盘砷致癌胎儿基础的表观遗传机制

• 批准号: 8360690
• 负责人: JERRY JIE LIU
• 金额: $ 5.89万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360690
• 关键词: Adult; Animal Model; Applications Grants; Arsenic; Binding; Biological Assay; Carcinogens; Cells; Coupled; Cytosine; DNA Methylation; Development; Disease; Epigenetic Process; Event; Exposure to; Fetus; Funding; Genes; Genetic; Grant; Human; Knowledge; Life; Liver neoplasms; Methylation; MicroRNAs; Modeling; Molecular; Monoclonal Antibodies; Mus; National Center for Research Resources; Perinatal Exposure; Pregnancy; Principal Investigator; Regulation; Research; Research Infrastructure; Resources; Site; Source; United States National Institutes of Health; Untranslated Regions; base; carcinogenesis; cost; developmental plasticity; drinking water; early life exposure; fetal; genome-wide; in utero; in vivo; interest; mature animal; next generation; novel; offspring; pregnant; tumor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 砷是一种已知的人类致癌物，但很难通过砷在成年动物中产生肿瘤 独自在生物测定中。我们已经开发了一种移植砷癌发生的动物模型。在这个 模型，从妊娠第8天到第18天，通过饮用水给怀孕的小鼠提供了无机砷， 后代在成年后出现了其他部位的肝肿瘤和肿瘤。确实，移植或早期生命 暴露于无机砷会诱导人类的肿瘤和其他疾病。的基础 砷癌发生的“发育起源”范式尚未完全定义，并且积累 证据表明表观遗传基础。该试点赠款提案的目的是利用全基因组 阐明砷引起的早期重编程的调节机制的方法。我们的 中心假设是在子宫砷暴露中响应的发育可塑性是顺序的 由表观遗传机制调节的事件，这对于肿瘤的遗传重编程至关重要 发展的晚期发展。 AIM 1将确定子宫砷诱导的DNA变化 甲基化。针对5-甲基化胞嘧啶的单克隆抗体将用于执行染色质抗沉淀 （芯片）与下一代测序结合以确定全基因组 子宫砷暴露导致甲基化改变。 AIM 2将确定子宫砷中的 microRNA的表达变化及其与3'-ITR感兴趣的基因的结合。提议 研究是新颖的，因为它将使用全基因组方法来阐明无机砷在 子宫在发育过程中调节表观遗传机制。拟议的研究很重要，因为 关于体内早期暴露期间砷癌发生的表观遗传调节知之甚少。这 成功完成砷引起的表观遗传变化的胎儿将产生关键知识 导致NIH赠款申请深入阐明移植砷的胎儿基础 致癌作用。