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

产前和产后早期逆境对墨西哥裔美国儿童表观基因组轨迹的共同和独特影响

• 批准号: 10665067
• 负责人: Andres Cardenas
• 金额: $ 59.36万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665067
• 关键词: 14 year old; 18 year old; Acceleration; Address; Adolescence; Affect; Age; Aging; Biological; Biological Markers; Biological Testing; Birth; Blood; California; Candidate Disease Gene; Cell Lineage; Cellular Structures; Child; Childhood; Chronic; Communities; Cues; DNA; DNA Methylation; Data; Development; Disease; Embryonic Development; Environment; Epidemic; Epigenetic Process; Exposure to; Face; Fetal Development; Future; Gene Expression; Genes; Genetic; Genotype; Goals; Health; Hispanic; Household; Immune system; Individual; Inflammatory; Latinx; Life; Longitudinal Studies; Low income; Measurement; Measures; Mediating; Mediation; Mediator; Mendelian randomization; Metabolic; Methods; Methylation; Mexican Americans; Minority; Minority Groups; Modeling; Morbidity - disease rate; Mothers; Not Hispanic or Latino; Obesity; Obesity Epidemic; Overweight; Pathway interactions; Pattern; Phase; Physiological; Predisposition; Prevalence; Psychosocial Factor; Public Health; Reporting; Research; Risk; Risk Factors; Role; Salinas Valley; Sampling; Social Environment; Statistical Methods; Testing; Tissues; Transcriptional Regulation; Variant; Weather; Writing; biological adaptation to stress; cohort; early childhood; early detection biomarkers; early life adversity; epigenetic marker; epigenome; epigenomics; fetal; field study; health assessment; health disparity; machine learning method; methylation biomarker; methylation pattern; methylome; minority communities; novel; obesity in children; obesity risk; offspring; postnatal; postnatal period; prenatal; prenatal influence; prenatal testing; programs; prospective; psychosocial stressors; racial disparity; response; social; social adversity; stressor; transcriptome sequencing; transcriptomics

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.

项目摘要 儿童肥胖是一种日益增长的公共卫生流行病，对西班牙裔儿童和 与发病率和下游健康差异有关。早期的广告和儿童时代的社会心理 已证明有措施会导致肥胖风险，报告的儿童的影响更大 在低收入家庭中。胎儿发育和早期生活的时期以动态和快速 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 童年和一般的身体发展。早期的贫穷社会环境一直是 假设有助于表观基因质的“风化”，从而加速了健康，衰老和 最终的健康差异，包括肥胖。健康差异起源的主要假设是 由于长期的广告暴露，广告在表观基因组上的生物嵌入。出现时 证据表明，社会心理压力源和广告与表观遗传生物标志物（如DNA）有关 甲基化，田间仍然存在显着局限性。也就是说，迄今为止的大多数研究都是横断面的 使用的候选基因方法，未研究整个表观遗传生物标志物的变化或轨迹 基因表达中的发育或功能后果。拟议的项目将利用数据，并 来自萨利纳斯（Chamacos）母亲和子女健康评估中心的样本，这是一个长期的 低收入拉丁裔的术语研究，主要是墨西哥裔美国人，居住在萨利纳斯山谷的母子对 加利福尼亚。我们已经重复测量和样品，用于出生时7、9、14的DNA甲基化分析和 在大约300对母子配对，遗传学和稳定的RNA中，在14年进行测序18年 年龄。我们将研究产前和产后早期生活广告指标至1）确定广告是否是否 措施与血液DNA甲基化轨迹和随后的基因表达变异有关。 2）评估广告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影响 纵向变化可能与肥胖风险有关； 3）确定DNA甲基化或 表观遗传衰老的媒体与肥胖症的关联以及是否可以从表观遗传广告分数中建立 儿童的血液甲基团。我们的研究将通过前瞻性测试假设来解决该领域的关键差距 在18年的时间里，解决了持久性和产后广告的持久性问题。我们将 测试表观遗传变化是否会在14年以外的未靶向RNA测序中影响基因表达。我们将 评估DNA甲基化是否可以作为早期广告的可靠生物标志物，否则 这些生物标志物是广告与肥胖风险与调解以及 孟德尔随机化方法。我们的方法将产生严格的数据以测试 社交广告及其在肥胖症患病率高的拉丁文，低收入出生队列中的后果。