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

项目概要 儿童肥胖是一种日益严重的公共卫生流行病，对西班牙裔儿童和儿童的影响尤为严重。 与发病率和下游健康差异相关。早年逆境和儿童心理社会 压力源已被证明会增加肥胖风险，据报道，对成长中的儿童影响更大 低收入家庭的比例上升。胎儿发育和生命早期的特点是动态和快速 胎儿DNA甲基化编程的变化、早期免疫系统相关基因的表观遗传成熟 童年和一般生理发育。早年的社会环境恶劣、恶劣 假设有助于表观基因组“风化”，导致健康、衰老和健康状况加速下降 最终的健康差异，包括肥胖。关于健康差异起源的一个主要假设是 由于长期暴露于逆境而将逆境生物嵌入到表观基因组中。新兴的同时 有证据表明，社会心理压力源和逆境与 DNA 等表观遗传生物标志物有关 甲基化，该领域仍然存在重大限制。也就是说，迄今为止大多数研究都是横断面的， 使用候选基因方法，没有研究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 样本来自萨利纳斯母婴健康评估中心 (CHAMACOS)，该中心是一个长期 对居住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 加利福尼亚州。我们在出生时、7 岁、9 岁、14 岁和 18 年对大约 300 对母子进行遗传学和稳定化 RNA 进行 14 年测序 年龄。我们将调查产前和产后的早期逆境措施，以 1) 确定逆境是否 测量值与血液 DNA 甲基化轨迹和随后的基因表达变化相关； 2）评估逆境措施是否影响表观遗传衰老时钟和生物标志物及其轨迹，以及是否 纵向变化与肥胖风险前瞻性相关； 3) 确定 DNA 甲基化或 表观遗传衰老介导与肥胖的关联，如果可以根据表观遗传逆境评分构建表观遗传逆境评分 儿童血液甲基化组。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差距 超过 18 年，解决产前和产后逆境的持续存在和根深蒂固的问题。我们会 14 岁时通过非靶向 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生命早期逆境的可靠生物标志物，或者如果 这些生物标志物与逆境和肥胖风险之间的关系有关，并通过调解和 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 社会逆境及其在肥胖率高的拉丁裔低收入出生群体中的后果。

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.