Epigenetic effects on susceptibility to heavy metal & PAH induced DNA damage

表观遗传对重金属敏感性的影响

基本信息

项目摘要

Heavy metals such as arsenic, nickel, and chromium as well as polycyclic aromatic hydrocarbons (PAHs) as benzo(a)pyrene are common environmental contaminants. Human exposure to such toxicants greatly increases cancer risk. The carcinogenicity of PAHs has been attributed to their covalent binding to DNA, which can result in mutations that ultimately lead to carcinogenesis. The mechanisms of metal-induced carcinogenesis are less clear. It has been found that nickel and arsenic exposure can induce DNA hypermethylation. Such non-mutational epigenetic changes could also result in suppression of tumor suppressor genes, such as the p53 gene, triggering tumorigenesis. Recently, we have found that the guanines at C5 cytosine methylated CpG sites are the major DNA targets of many PAHs, including benzo(a)pyrene diol epoxide (BPDE). In fact, we have found that the BPDE binding spectrum in the tumor suppressor p53 gene coincides with the mutation spectrum of this gene in lung cancer. It has been found that a mutated p53 gene is sufficient to trigger carcinogenesis in animal models, and that more importantly, 50% of human cancers have a mutation in the p53 gene. These findings have lead us to hypothesize that targeted DNA damage, rather than selection, is the major determinant of the p53 mutation spectrum in cancer, and that the CpG selection, is the major determinant of the p53 mutation spectrum in human cancer, and that the CpG methylation status of an individual p53 gene may determine the susceptibility of this gene to DNA damage and mutation. These findings have led us to hypothesize that targeted DNA damage, rather than selection, is the major determinant of the p53 mutation spectrum in human cancer, and that the CpG methylation status of an individual p53 gene may determine the susceptibility of this gene to DNA damage and mutation. In light of these findings, we propose that the carcinogenicity of nickel, arsenic and chromium may be partly due to their ability to induce DNA hypermethylation, which in turn enhances the susceptibility of methylated tumor suppressor genes and protooncogenes to bulky carcinogen-induced DNA damage and mutations. The objective of this research is to test the hypothesis using two state-of-the-art technologies; UvrABC-ligation-mediated-PCR to map DNA adducts at the single nucleotide level, and the p53 GeneChip to detect mutations and cytosine methylation. We will determine: 1) the p53 gene methylation status in lymphocytes of different individuals and assess its relationship with the susceptibility to BDE damage, 2) whether nickel, arsenic, and chromium induce changes in the methylation status of the p53 gene and whether nickel, arsenic, and chromium induce changes in the methylation status of the p53 gene and, consequently, in the susceptibility of this gene to BPDE induced-DNA damage, and 3) the effect of nickel, arsenic and chromium treatment on the repair of BPDE-DNA adducts in the p53, beta-actin and HPRT gene.
砷、镍、铬等重金属以及苯并(a)芘等多环芳烃是常见的环境污染物。人类接触这些有毒物质会大大增加患癌症的风险。多环芳烃的致癌性归因于它们与DNA的共价结合,这可能导致突变,最终导致致癌。金属诱导的致癌机制尚不清楚。研究发现,镍和砷暴露可诱导DNA高甲基化。这种非突变的表观遗传变化也可能导致肿瘤抑制基因(如p53基因)的抑制,从而引发肿瘤发生。最近,我们发现C5胞嘧啶甲基化CpG位点的鸟嘌呤是许多多环芳烃的主要靶位,包括苯并(a)芘二醇环氧化物(BPDE)。事实上,我们已经发现肿瘤抑制基因p53中的BPDE结合谱与肺癌中该基因的突变谱一致。已经发现,突变的p53基因足以在动物模型中引发致癌作用,更重要的是,50%的人类癌症在p53基因中具有突变。这些发现使我们假设靶向DNA损伤而不是选择是癌症中p53突变谱的主要决定因素,并且CpG选择是人类癌症中p53突变谱的主要决定因素,并且单个p53基因的CpG甲基化状态可能决定该基因对DNA损伤和突变的易感性。这些发现使我们假设靶向DNA损伤,而不是选择,是人类癌症中p53突变谱的主要决定因素,并且单个p53基因的CpG甲基化状态可能决定该基因对DNA损伤和突变的易感性。根据这些发现,我们认为镍、砷和铬的致癌性可能部分是由于它们诱导DNA超甲基化的能力,这反过来又增强了甲基化的肿瘤抑制基因和原癌基因对大体积致癌物诱导的DNA损伤和突变的易感性。本研究的目的是使用两种最先进的技术来验证这一假设; UvrABC连接介导的PCR在单核苷酸水平上绘制DNA加合物,以及p53基因芯片检测突变和胞嘧啶甲基化。我们将确定:1)不同个体淋巴细胞中p53基因甲基化状态,并评估其与BDE损伤易感性的关系,2)镍、砷和铬是否诱导p53基因甲基化状态的变化,以及镍、砷和铬是否诱导p53基因甲基化状态的变化,从而导致该基因对BPDE诱导的DNA损伤易感性的变化,镍、砷和铬处理对p53、β-肌动蛋白和HPRT基因中BPDE-DNA加合物修复的影响。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Eric Moon-shong M. TANG其他文献

Eric Moon-shong M. TANG的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Eric Moon-shong M. TANG', 18)}}的其他基金

Project 2: E-cigarette Smoke Induced Bladder Carcinogenesis and Invasive Cancer Development
项目2:电子烟烟雾诱发膀胱癌发生和侵袭性癌症发展
  • 批准号:
    10455730
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Project 2: E-cigarette Smoke Induced Bladder Carcinogenesis and Invasive Cancer Development
项目2:电子烟烟雾诱发膀胱癌发生和侵袭性癌症发展
  • 批准号:
    10661064
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Core B: Reagent/Service Core
核心 B:试剂/服务核心
  • 批准号:
    10229416
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
DNA Repair and Tobacco Smoke in Bladder Carcinogenesis
DNA 修复和烟草烟雾在膀胱癌发生中的作用
  • 批准号:
    8596898
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Core B: Reagent/Service Core
核心 B:试剂/服务核心
  • 批准号:
    10455733
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Project 2: E-cigarette Smoke Induced Bladder Carcinogenesis and Invasive Cancer Development
项目2:电子烟烟雾诱发膀胱癌发生和侵袭性癌症发展
  • 批准号:
    10229413
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Core B: Reagent/Service Core
核心 B:试剂/服务核心
  • 批准号:
    10661071
  • 财政年份:
    2013
  • 资助金额:
    $ 16.41万
  • 项目类别:
Pilot Projects
试点项目
  • 批准号:
    8053425
  • 财政年份:
    2010
  • 资助金额:
    $ 16.41万
  • 项目类别:
Lipid peroxidation product induced DNA damage in the p53 gene and liver cancer
脂质过氧化产物诱导 p53 基因 DNA 损伤和肝癌
  • 批准号:
    7905832
  • 财政年份:
    2006
  • 资助金额:
    $ 16.41万
  • 项目类别:
Pilot Projects
试点项目
  • 批准号:
    7320068
  • 财政年份:
    2006
  • 资助金额:
    $ 16.41万
  • 项目类别:

相似海外基金

Source and homeostatic functions of anti-adduct IgM in humans
人类抗加合物 IgM 的来源和稳态功能
  • 批准号:
    10680950
  • 财政年份:
    2023
  • 资助金额:
    $ 16.41万
  • 项目类别:
DNA Adduct Detection and Repair in Mammalian Cells
哺乳动物细胞中 DNA 加合物的检测和修复
  • 批准号:
    10653232
  • 财政年份:
    2021
  • 资助金额:
    $ 16.41万
  • 项目类别:
DNA Adduct Detection and Repair in Mammalian Cells
哺乳动物细胞中 DNA 加合物的检测和修复
  • 批准号:
    10299723
  • 财政年份:
    2021
  • 资助金额:
    $ 16.41万
  • 项目类别:
Identify the DNA Adduct and Associated Metabolic Alterations in Bladder Cancer of Smokers
鉴定吸烟者膀胱癌中的 DNA 加合物和相关代谢改变
  • 批准号:
    10371068
  • 财政年份:
    2018
  • 资助金额:
    $ 16.41万
  • 项目类别:
Elucidation of novel benzo (a) pyrene DNA adduct formation mechanism and search for genotoxicity preventive foods.
阐明新型苯并(a)芘DNA加合物形成机制并寻找遗传毒性预防食品。
  • 批准号:
    18K06736
  • 财政年份:
    2018
  • 资助金额:
    $ 16.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identify the DNA Adduct and Associated Metabolic Alterations in Bladder Cancer of Smokers
鉴定吸烟者膀胱癌中的 DNA 加合物和相关代谢改变
  • 批准号:
    9895423
  • 财政年份:
    2018
  • 资助金额:
    $ 16.41万
  • 项目类别:
Investigating protein adduct formation from exposure to perfluoroalkyl substances
研究暴露于全氟烷基物质中蛋白质加合物的形成
  • 批准号:
    516485-2017
  • 财政年份:
    2017
  • 资助金额:
    $ 16.41万
  • 项目类别:
    Canadian Graduate Scholarships Foreign Study Supplements
Arylamine DNA adduct recognition in eukaryotic nucleotide excision repair
真核核苷酸切除修复中芳胺 DNA 加合物识别
  • 批准号:
    9372223
  • 财政年份:
    2017
  • 资助金额:
    $ 16.41万
  • 项目类别:
Generation and characterization of adduct-specific anti cisplatin DNA antibodies
加合物特异性抗顺铂 DNA 抗体的生成和表征
  • 批准号:
    8951743
  • 财政年份:
    2015
  • 资助金额:
    $ 16.41万
  • 项目类别:
Carcinogen DNA adduct biomarkers in formalin fixed tissues
福尔马林固定组织中的致癌物 DNA 加合物生物标志物
  • 批准号:
    8737541
  • 财政年份:
    2014
  • 资助金额:
    $ 16.41万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了