Common and Distinct Influences of Prenatal and Postnatal Early-Life Adversity on Epigenomic Trajectories in Mexican American Children

项目总结 儿童肥胖是一种日益严重的公共卫生流行病，它不成比例地影响着拉美裔儿童和 与发病率和下游健康差距有关。早期生活逆境与童年心理社会 压力因素已被证明是肥胖风险的因素，据报道，在儿童中的影响更大。 在低收入家庭中。胎儿发育和早期生命的特点是动态和快速 早期胎儿DNA甲基化编程、免疫系统相关基因表观遗传成熟的变化 儿童期和一般生理发展。早年生活中恶劣的社会环境 假设有助于表观基因组的“风化”，导致健康加速下降，衰老和 最终的健康差距，包括肥胖。关于健康差距起源的一个主要假说是 由于慢性逆境暴露，逆境在表观基因组上的生物嵌入。在出现的同时 有证据表明，心理社会压力和逆境与表观遗传生物标记物如DNA有关。 甲基化，这一领域仍然存在重大限制。也就是说，到目前为止，大多数研究都是横断面的， 使用候选基因方法，而不是研究整个表观遗传生物标志物的变化或轨迹 发育，或基因表达的功能后果。拟议的项目将利用数据和 萨利纳斯母亲和儿童健康评估中心(CHAMACOS)的样本，这是一个长期- 生活在萨利纳斯山谷的低收入拉丁裔(主要是墨西哥裔美国人)母子对的学期研究 来自加利福尼亚州。我们在出生时重复测量和样本DNA甲基化分析，7，9，14和 18年在大约300对母子中，遗传学和稳定的RNA测序在14年 年龄。我们将调查出生前和出生后的早期逆境测量，以1)确定逆境 测量方法与血液DNA甲基化轨迹和随后基因表达的变化有关； 2)评估逆境措施是否影响表观遗传衰老时钟和生物标记物及其轨迹 纵向变化可能与肥胖风险相关；以及3)确定DNA甲基化或 表观遗传衰老与肥胖的关系以及表观遗传逆境评分是否可以从 儿童血液中的甲基组。我们的研究将通过前瞻性地检验假设来解决该领域的关键空白。 超过18年，并解决持续存在和嵌入出生前和出生后逆境的问题。我们会 在14年后用非靶向RNA测序测试表观遗传变化是否影响基因表达。我们会 评估DNA甲基化是否可以作为早期生活中逆境的可靠生物标记物 这些生物标志物是逆境和肥胖风险之间关系的因果关系，通过中介和 孟德尔随机化方法。我们的方法将产生严格的数据来测试生物嵌入 社会逆境及其在拉丁裔低收入出生队列中的后果，肥胖率很高。

PROJECT SUMMARY Childhood obesity is a growing public health epidemic that is disproportionally affecting Hispanic children and associated with morbidity and downstream health disparities. Early-life adversity and childhood psychosocial stressors have been shown to contribute to obesity risk, with stronger effects reported among children growing up in lower-income households. The period of fetal development and early-life are marked by dynamic and rapid changes in fetal DNA methylation programming, epigenetic maturation of immune system-related genes in early- childhood and general physiological development. A poor and adverse social environment in early life has been hypothesized to contribute to epigenomic “weathering” leading to accelerated decline in health, aging and eventual health disparities, including obesity. A leading hypothesis for the origins of health disparities is the biological embedding of adversity on the epigenome due to chronic adversity exposure. While emerging evidence indicates that psychosocial stressors and adversity are associated with epigenetic biomarkers like DNA methylation, significant limitations remain in the field. Namely, most studies to date have been cross-sectional, used candidate gene approaches, not investigated changes or trajectories in epigenetic biomarkers throughout development, or functional consequences in gene expression. The proposed project will leverage data and samples from The Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a long- term study of low-income Latinx, predominantly Mexican American, mother-child pairs living in the Salinas Valley of California. We have repeated measurements and samples for DNA methylation analyses at birth, 7, 9, 14 and 18 years in approximately 300 mother-child pairs, genetics, and stabilized RNA for sequencing at 14 years of age. We will investigate both pre- and postnatal early-life adversity measures to 1) determine if adversity measures are associated with blood DNA methylation trajectories and subsequent variation in gene expression; 2) evaluate if adversity measures influence epigenetic aging clocks and biomarkers and their trajectories and if longitudinal changes are prospectively associated with obesity risk; and 3) determine if DNA methylation or epigenetic aging mediate associations with obesity and if an epigenetic adversity score can be constructed from children’s blood methylome. Our study will address critical gaps in the field by testing hypotheses prospectively over 18 years and addressing questions of persistence and embedment of pre- and postnatal adversity. We will test if epigenetic changes influence gene expression with untargeted RNA sequencing at 14 years. We will evaluate if DNA methylation can serve as a reliable biomarker of adversity in early-life and or alternatively if these biomarkers are causal for the relationship between adversity and obesity risk with mediation and mendelian randomization methods. Our approach will yield rigorous data to test the biological embedment of social adversity and its consequences in a Latinx, low-income birth cohort with high obesity prevalence.