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: 10523031
• 负责人: Andres Cardenas
• 金额: $ 61.77万
• 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/10523031
• 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 of activation protein; 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; Prevalence; Psychosocial Factor; Public Health; Reporting; Research; Risk; Risk Factors; Role; Salinas Valley; Sampling; Social Environment; Statistical Methods; Testing; Tissues; Transcriptional Regulation; Variant; Weather; biological adaptation to stress; biomarker signature; 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有关。 压力源已被证明会增加肥胖风险，据报告，对成长中的儿童影响更大 胎儿发育和早期生命的特点是动态和快速的。 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 童年时期和一般的生理发育受到不良和不利的社会环境的影响。 加速促进表观基因组“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。健康差异起源的一个主要假设是 由于长期的逆境暴露而在表观基因组中嵌入逆境。 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局限性，即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 拟议的项目将利用数据和基因表达的发展或功能后果。 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 我们在出生时、7 岁、9 岁、14 岁和 14 岁时重复进行了 DNA 甲基化分析测量和样本。 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 我们将调查产前和产后的早期逆境措施，以 1) 确定逆境是否存在。 测量结果与血液 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 我们的研究将通过前瞻性检验假设来解决该领域的关键空白。 超过 18 年，并解决产前和产后逆境的持续性和根深蒂固的问题。 我们将在 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。 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，或者是否 这些生物标志物是逆境与肥胖风险之间关系的因果关系 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。