Impact of transplacental PAH exposure on the epigenome

经胎盘 PAH 暴露对表观基因组的影响

• 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
• 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

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（PAHs）是对人类健康“重新出现”的威胁。尽管在美国，通过吸烟接触多环芳烃的情况正在减少，但人类每天接触多环芳烃的情况却在增加，这可能是由于中国和美国煤炭工业的大规模扩张。人们非常担心，胎儿在怀孕期间接触环境中的化学物质可能与成人癌症有关。环境中的多环芳烃（PAHs）二苯并[a， 1]芘（DBP）和苯并[a]芘（BaP）都是小鼠胎盘移植致癌物，导致成年后代肺部肿瘤的高发。许多癌症都与表观基因组的改变有关。肿瘤的表观遗传变化主要导致基因启动子区域的异常超甲基化和不适当的基因沉默，从而赋予肿瘤细胞选择优势。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）。来自体外细胞培养研究的新证据表明，BaP改变了基因特异性启动子甲基化的模式。然而，目前尚不清楚体内暴露于多环芳烃是否会改变表观基因组从而增加癌症风险。为了解决这一重要的知识差距，我们建议在经胎盘肺化学致癌模型中研究妊娠期多环芳烃暴露的影响。本提案的主要目的是确定妊娠期暴露于多环芳烃对小鼠肺中胎儿和成年后代表观基因组的影响。目前的假设是，经胎盘暴露于多环芳烃会改变关键肿瘤抑制基因启动子区域的DNA甲基化，从而增加成人患肺癌的风险。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对新生儿小鼠肺中Cdkn2a、Rarb、Dapk1、Mgmt和Cadh13基因启动子区域甲基化的影响；评估宫内暴露于多环芳烃对新生儿肺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 - 45周龄）肿瘤前病变发展为肺腺癌时基因启动子甲基化，评估妊娠期多环芳烃暴露导致肿瘤抑制基因沉默的时间；将改变的DNA甲基化与改变的基因和蛋白质表达联系起来。这项研究的成功完成将提供关于多环芳烃对表观基因组影响的新知识，并建立胎儿接触多环芳烃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暴露于多环芳烃会导致表观基因组的持续变化，从而增加成人患癌症的风险。