Impact of transplacental PAH exposure on the epigenome

描述（由申请人提供）：多环芳烃（PAH）代表了对人类健康的“重新出现”威胁。尽管美国通过烟草烟雾接触多环芳烃的情况正在减少，人类每天暴露于多环芳烃的数量正在增加，这可能是由于中国和美国煤电工业的巨大扩张。人们非常担心胎儿在怀孕期间暴露于环境化学品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，可导致成年子代肺肿瘤的高发病率。表观基因组的改变与许多癌症有关。肿瘤中的表观遗传学改变主要导致基因启动子区域的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。肿瘤抑制基因的超甲基化已在人类和小鼠肺癌中显示，包括细胞周期蛋白依赖性激酶抑制剂2A（Cdkn 2a）、视黄酸受体β（Rarb）、死亡相关蛋白激酶（Dapk 1）、O-6-甲基鸟嘌呤DNA甲基转移酶（Mgmt）和H-钙粘蛋白（Cadh 13）。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以增加癌症风险。为了解决这一重大的知识差距，我们建议研究妊娠期多环芳烃暴露在经胎盘模型的肺化学致癌作用的影响。该建议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。工作假设是经胎盘暴露于多环芳烃改变了关键肿瘤抑制基因启动子区域的DNA甲基化，导致成人肺癌风险增加。我们计划通过以下具体目标来实现我们的主要目标：（1）确定DBP和BaP经胎盘暴露对新生小鼠肺中Cdkn 2a，Rarb，Dapk 1，Mgmt和Cadh 13基因启动子区域甲基化的影响;评估宫内暴露于PAHs对新生小鼠肺中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 - 45周龄）的基因启动子甲基化，评估妊娠期PAH暴露导致的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。成功完成拟议的研究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的潜在表观遗传联系。如果这一假设得到支持，这将是第一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，从而导致成年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联系在一起。新的科学表明，环境因素可能会改变表观基因组（即影响基因表达的DNA结构和修饰的特定模式），从而增加癌症风险。一生中暴露于化学致癌物的很大一部分发生在怀孕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。

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.