Exploring persistent epigenetic changes after prenatal famine exposure in humans

描述(由研究人员提供)：本申请涉及广泛的挑战领域：08：基因组学，以及具体的挑战资助主题：08-AG-105**：研究关键发育时期个人行为、社会和物理环境以及遗传/表观遗传过程之间相互作用的方法。项目标题：出生前的早期生命暴露和成人表观遗传学广泛的流行病学证据已将许多早期生命和环境因素与成人发病疾病联系起来。环境如何改变晚年的疾病风险，一个看似合理的机制是通过对体细胞的表观遗传效应，导致关键途径中关键基因的激活或沉默。DNA甲基化是一种表观遗传学改变，通过改变基因产生的蛋白质，可能在疾病病因中发挥重要作用。因此，拥有相同基因的人，比如双胞胎，可能会因为DNA甲基化的不同变化而产生不同的疾病结果，这些变化会影响特定基因产生特定蛋白质的能力。人类研究支持DNA甲基化模式随年龄变化，动物研究支持关键时期的暴露可以改变表观遗传事件。然而，到目前为止，通过检查关键时期(包括产前和生命早期)的暴露以及生命后期的DNA甲基化模式，很少有机会将这两条证据在人类身上联系起来。我们最近完成了第一项人类研究，表明出生体重等早期生活因素与多种族出生队列中女性中年测得的基因组DNA甲基化之间存在关联(1)，也是第一项研究表明，在暴露于产前饥荒环境后，IGF2基因的DNA甲基化存在持久的表观遗传学差异(2)。利用从荷兰出生于1944-1945年的三个出生队列中获得的产前饥荒暴露的成人随访资源，以及从未暴露的时间对照和兄弟姐妹对照(n=971；437名男性和537名女性)中收集的资源，我们现在建议检查一方面怀孕期间和怀孕不同阶段的母亲饥荒暴露与成年期DNA甲基化模式之间的关系。我们将进一步研究成年期的DNA甲基化模式与心血管疾病和糖尿病的疾病风险因素之间的关系，如肥胖、血胆固醇升高或空腹血糖值。因为一些研究表明，早期环境和长期健康结果之间的关系在男性和女性中可能是不同的，我们将按性别比较这些模式。表观遗传学领域在帮助我们了解人类疾病的基础方面大有可为，特别是环境暴露如何进入体内导致疾病。表观遗传学也可能有助于解释不同人群之间的疾病差异，因此对于理解环境暴露如何可能导致健康差异可能是重要的。根据过去在关键时期收集的信息，结合今天可靠的DNA甲基化标记，以强有力的暴露措施进行大规模流行病学研究是必要的第一步。此类研究只能由了解生物学机制和方法学问题的多学科团队进行。我们的团队在美国和国外的生命课程研究的设计和分析方面拥有广泛的专业知识，并且非常 在处理关键时期、DNA甲基化和多种疾病后果等方法学问题方面经验丰富。除了实现科学目标外，这笔挑战赠款还将支持保留一名在DNA甲基化分析方面具有专业知识的高级实验室科学家和两名分别在统计学和生命过程方法方面具有专业知识的硕士级别分析师，并为研究团队提供资金，以便现在将表观遗传学方法纳入他们正在进行的对这些独特的出生队列的分析中。这将与继续调查生命早期接触对健康的终身影响密切相关。越来越多的证据表明，表观遗传变化，包括DNA甲基化，可能在心血管疾病、癌症和其他慢性疾病的发展中发挥重要作用。与基因不同，表观遗传模式可能会受到环境的影响，并在生命过程中发生变化。此外，表观遗传模式可能会通过风险因素的变化而逆转，因为人类和动物的研究都报告了产前和早期生命暴露与成年后DNA甲基化之间的关联。 公共卫生相关性：这项研究将利用出生于1944-1945年的男性和女性的预期出生队列，在接下来的两年里检查产前环境，特别是孕妇怀孕期间的营养是否与成年后基因组DNA甲基化水平的变化有关。我们将进一步调查成年期的基因组DNA甲基化水平是否与心血管疾病风险的临床指标相关，如血压、血脂水平、空腹血糖水平和肥胖。这项研究所需的体检记录和生物材料已事先收集并储存，等待资助的资金将立即可供分析。

DESCRIPTION (provided by investigator): This application addresses the broad Challenge Area: 08: Genomics, and the specific Challenge Grant Topic: 08-AG-105**: Approaches to study the interactions among individual behaviors, social and physical environments, and genetic/epigenetic processes during critical developmental periods. Project Title: Early Life Exposures before Birth and Adult Epigenetics Extensive epidemiologic evidence has linked many early life and environmental factors to adult- onset diseases. One plausible mechanism how the environment could alter disease risk later in life is through epigenetic effects on somatic cells, leading to activation or silencing of key genes in critical pathways. DNA methylation, one type of epigenetic change, may play an important role in disease causation by altering the proteins that are produced by genes. Thus, people with identical genes, like twins, may have different disease outcomes because of differential changes in DNA methylation that affect the ability of specific genes to produce specific proteins. Human studies have supported that DNA methylation patterns change with age and animal studies have supported that exposures during critical periods can alter epigenetic events. However, until now, there have been few opportunities to link these two lines of evidence in humans by examining exposures during critical periods including the prenatal and early life periods and DNA methylation patterns latter in life. We have recently completed the first study in humans showing associations between early life factors such as birth weight and genomic DNA methylation measured in mid-life among women in a multiethnic birth cohort (1) and also the first study to show that there are persistent epigenetic differences in DNA methylation of the IGF2 gene after exposure to a prenatal famine environment (2). Using resources from an adult follow-up already collected from three birth cohorts in the Netherlands with prenatal famine exposure in born in 1944-1945 and from unexposed time controls and sibling controls (n= 971; 437 men and 537 women), we now propose to examine the associations between maternal famine exposure in the periconceptional period and in different stages of pregnancy on the one hand and DNA methylation patterns in adulthood on the other. We will further examine how the DNA methylation patterns in adulthood are related to disease risk factors for cardio-vascular disease and diabetes such as obesity, elevated blood cholesterol or fasting glucose values. Because some studies suggest that the relation between the early environment and long-term health outcomes may be different in men and women, we will compare these patterns by gender. The field of epigenetics holds great promise in helping us understand the basis of human disease and in particular how environmental exposures can get inside the body to cause disease. Epigenetics may also help explain differences in disease across populations and therefore may be important in understanding how environmental exposures may contribute to health disparities. Conducting large epidemiologic studies with robust measures of exposures based on information already collected in the past during critical periods combined with reliable markers of DNA methylation today are a necessary first step. Such studies can only be conducted by multidisciplinary teams with an understanding of biological mechanisms and methodological issues. Our team has extensive expertise in the design and analysis of life course studies in the US and abroad and is very experienced in dealing with the many methodological issues of critical periods, DNA methylation, and multiple disease outcomes. This challenge grant in addition to accomplishing the scientific aims will support the retention of a senior laboratory scientist with expertise in DNA methylation assays and two Masters level analysts with expertise in statistics and life course methods respectively, as well as provide funding to the investigator team to now include epigenetic approaches in their ongoing analyses of these unique birth cohorts. This will be highly relevant for the continuing investigation of the lifelong impact of even early lifetime exposures on health. A growing body of evidence indicates that epigenetic changes, including DNA methylation, may play an important role in the development of cardiovascular disease, cancer and other chronic conditions. In contrast to genes, epigenetic patterns may be affected by the environment and change over the life course. Further, epigenetic patterns may be reversed through changes in risk factors, as both human and animal studies have reported associations between prenatal and early life exposures and DNA methylation in adulthood. PUBLIC HEALTH RELEVANCE: This study will make use of a prospective birth cohort of women and men born in 1944-1945 to examine in the next two years whether the prenatal environment and specifically maternal nutrition in pregnancy are associated with changes in genomic DNA methylation levels in adulthood. We will further investigate if genomic DNA methylation levels in adulthood are associated with clinical indicators for cardiovascular disease risk such as blood pressure, lipid levels, fasting blood sugar levels, and obesity. The required medical examination records and biological materials for this study have been previously collected and stored and pending funding will be immediately available for analysis.