Impact of transplacental PAH exposure on the epigenome

经胎盘 PAH 暴露对表观基因组的影响

基本信息

批准号：
7876561
负责人：
Abby D Benninghoff
金额：
$ 7万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7876561
关键词：
3-Methylcholanthrene Address Adult Adult Children Age Aromatic Polycyclic Hydrocarbons Asia Benzo(a)pyrene Breast Feeding CDKN2A gene Carcinogens Cell Culture Techniques Chemicals China Chronic Coal Cyclin-Dependent Kinase Inhibitor 2A DAP kinase DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Structure Disease Energy-Generating Resources Environmental Exposure Epigenetic Process Exposure to Fetus Foundations Gene Expression Gene Proteins Gene Silencing Generations Genes Goals H-Cadherin Health Human Hypermethylation In Vitro Incidence Industry International Agency for Research on Cancer Knowledge Laboratories Lesion Link Liver neoplasms Lung Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Maternal-Fetal Exchange Measures Methylation Methyltransferase Gene Modeling Modification Mus Neonatal O(6)-Methylguanine-DNA Methyltransferase O-(6)-methylguanine Pacific Ocean Pattern Perinatal Exposure Petroleum Pregnancy Promoter Regions Pyrenes Research Risk Science Time Tobacco smoke Tumor Suppressor Genes Work aged cancer cell cancer risk carcinogenesis cell transformation chemical carcinogen chemical carcinogenesis environmental agent environmental carcinogenesis environmental chemical exposed human population fetal human RARB protein in vivo innovation lung carcinogenesis male neonate neoplastic cell promoter protein expression public health relevance response tumor

项目摘要

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) represent a "re-emerging" threat to human health. Even though exposure to PAHs via tobacco smoke is decreasing in the U.S., daily human exposures to PAHs are on the rise, likely due to the vast expansion of the coal power industry in China and the U.S. There is great concern that fetal exposure to environmental chemicals during pregnancy could be linked to adult cancers. The environmental PAHs dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BaP) are both transplacental carcinogens in mice causing a high incidence of lung tumors in adult offspring. Alterations of the epigenome have been implicated in many cancers. Epigenetic changes in tumors mostly result in aberrant hypermethylation of gene promoter regions and inappropriate gene silencing, thus conferring a selective advantage to neoplastic cells. Hypermethylation of tumor suppressor genes has been shown in human and mouse lung cancers, including cyclin-dependent kinase inhibitor 2A (Cdkn2a), retinoic acid receptor beta (Rarb), death-associated protein kinase (Dapk1), O-6-methylguanine DNA methyltransferase (Mgmt) and H-cadherin (Cadh13). New evidence from in vitro cell culture studies suggests that BaP alters patterns of gene-specific promoter methylation. However, it is not known whether in vivo exposure to PAHs alters the epigenome to increase cancer risk. To address this significant knowledge gap, we propose to investigate the impact of gestational PAH exposure in a transplacental model of lung chemical carcinogenesis. The primary objective of this proposal is to determine the impact of gestational exposure to PAHs on the fetal and adult offspring epigenome in the mouse lung. The working hypothesis is that transplacental exposure to PAHs alters DNA methylation in the promoter region of key tumor suppressor genes leading to increased risk of lung cancer in the adult. We plan to accomplish our primary objective by pursuing the following specific aims: (1) Determine the impact of transplacental exposure to DBP and BaP on methylation of the promoter regions of the Cdkn2a, Rarb, Dapk1, Mgmt and Cadh13 genes in neonate mouse lung; assess impact of in utero exposure to PAHs on expression of DNA methyltransferase genes 1, 3a and 3b in neonate lung. (2) Assess the timing of tumor suppressor gene silencing resulting from gestational PAH exposure by measuring gene promoter methylation in adult mice (aged 15 to 45 weeks) as preneoplastic lesions develop into lung adenocarcinomas in the adults; functionally link altered DNA methylation to altered gene and protein expression. Successful completion of the proposed research will provide new knowledge about the impact of PAHs on the epigenome and establish potential epigenetic links between fetal exposure and adult disease. Should the hypothesis be supported, this would be the first demonstration that fetal exposure to PAHs causes persistent changes in the epigenome leading to increased cancer risk in the adult. PUBLIC HEALTH RELEVANCE: There is great need to understand how environmental exposures during pregnancy may be linked to adult disease. New science suggests that environmental agents may modify the epigenome (that is, specific patterns of DNA structure and modifications that influence gene expression) to increase cancer risk. A significant portion of lifetime exposure to chemical carcinogens occurs during gestation and throughout breast feeding, and the fetus may be particularly susceptible to chemicals that alter the epigenome.

描述（由申请人提供）：多环芳烃（PAH）对人类健康构成“重新出现”的威胁。尽管在美国，通过烟草烟雾接触多环芳烃的人数正在减少，但人类每日接触多环芳烃的人数却在增加，这可能是由于中国和美国煤电行业的大规模扩张。人们非常担心胎儿接触环境化学物质怀孕期间的癌症可能与成人癌症有关。环境中的多环芳烃二苯并[a,l]芘（DBP）和苯并[a]芘（BaP）都是小鼠经胎盘致癌物，导致成年后代肺部肿瘤的高发病率。表观基因组的改变与许多癌症有关。肿瘤的表观遗传变化主要导致基因启动子区域异常高甲基化和不适当的基因沉默，从而赋予肿瘤细胞选择性优势。肿瘤抑制基因的高甲基化已在人类和小鼠肺癌中得到证实，包括细胞周期蛋白依赖性激酶抑制剂 2A (Cdkn2a)、视黄酸受体 β (Rarb)、死亡相关蛋白激酶 (Dapk1)、O-6-甲基鸟嘌呤 DNA 甲基转移酶(Mgmt) 和 H-钙粘蛋白 (Cadh13)。体外细胞培养研究的新证据表明 BaP 改变基因特异性启动子甲基化模式。然而，尚不清楚体内接触多环芳烃是否会改变表观基因组从而增加癌症风险。为了解决这一重大知识差距，我们建议研究妊娠期 PAH 暴露对经胎盘的肺癌化学致癌模型的影响。该提案的主要目的是确定妊娠期接触多环芳烃对小鼠肺部胎儿和成年后代表观基因组的影响。目前的假设是，经胎盘接触 PAH 会改变关键抑癌基因启动子区域的 DNA 甲基化，导致成人患肺癌的风险增加。我们计划通过追求以下具体目标来实现我们的主要目标：（1）确定经胎盘暴露于 DBP 和 BaP 对新生小鼠肺中 Cdkn2a、Rarb、Dapk1、Mgmt 和 Cadh13 基因启动子区域甲基化的影响；评估子宫内接触 PAH 对新生儿肺中 DNA 甲基转移酶基因 1、3a 和 3b 表达的影响。 (2) 通过测量成年小鼠（15至45周）的基因启动子甲基化，评估妊娠期PAH暴露导致肿瘤抑制基因沉默的时间，因为成年小鼠的癌前病变发展为肺腺癌；在功能上将改变的 DNA 甲基化与改变的基因和蛋白质表达联系起来。拟议研究的成功完成将提供有关多环芳烃对表观基因组影响的新知识，并建立胎儿暴露与成人疾病之间潜在的表观遗传联系。如果这一假设得到支持，这将是首次证明胎儿接触多环芳烃会导致表观基因组持续变化，从而导致成人患癌症的风险增加。公共卫生相关性：非常需要了解怀孕期间的环境暴露如何与成人疾病相关。新科学表明，环境因素可能会改变表观基因组（即影响基因表达的 DNA 结构的特定模式和修饰），从而增加癌症风险。一生中接触化学致癌物的很大一部分发生在妊娠期间和整个母乳喂养期间，胎儿可能特别容易受到改变表观基因组的化学物质的影响。