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.

项目摘要 儿童肥胖症是一种日益严重的公共卫生流行病，严重影响西班牙裔儿童， 与发病率和下游健康差距有关。早期生活逆境与儿童社会心理 压力因素已被证明有助于肥胖风险，据报道， 在低收入家庭。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， 儿童期和一般生理发育。早年生活中贫穷和不利的社会环境， 假设有助于表观基因组“风化”，导致健康，衰老和 最终的健康差异，包括肥胖。关于健康差距起源的一个主要假设是， 由于长期逆境暴露，逆境在表观基因组上的生物嵌入。而新兴 有证据表明，心理社会压力和逆境与DNA等表观遗传生物标志物有关， 甲基化，在该领域中仍然存在显著的限制。也就是说，迄今为止的大多数研究都是横断面的， 使用候选基因方法，未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性后果。拟议项目将利用数据， 来自萨利纳斯母亲和儿童健康评估中心（CHAMACOS）的样本， 长期研究低收入拉丁裔，主要是墨西哥裔美国人，母亲和孩子对生活在萨利纳斯山谷 在加州。我们在出生时、7、9、14和15进行了重复测量和DNA甲基化分析的样本。 在大约300对母子中进行了18年的遗传学研究，并在14岁时进行了稳定的RNA测序。 年龄我们将调查出生前和出生后早期生活逆境的措施，以1）确定逆境是否 测量与血液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， 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，如果表观遗传逆境评分可以从 儿童血液甲基化我们的研究将通过前瞻性地测试假设来解决该领域的关键空白 18年来，致力于解决产前和产后逆境的持续性和嵌入性问题。我们将 测试表观遗传变化是否影响14岁时非靶向RNA测序的基因表达。我们将 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 这些生物标志物是逆境和肥胖风险之间的因果关系， 孟德尔随机化方法。我们的方法将产生严格的数据，以测试生物嵌入 社会逆境及其后果在拉丁裔，低收入出生队列与高肥胖患病率。