Prenatal Longitudinal Metabolomics Profiling for Early Childhood Growth Trajectories and Obesity Risk in a US Biracial Birth Cohort

儿童肥胖仍然是最严重的公共卫生挑战之一，因为它持续居高不下 流行率和不良健康后果。迫切需要新的生物标志物来预测 为儿童肥胖的早期预防提供有效的干预靶点。尽管一个不断增长的 大量证据有力地支持了孕期孕妇的状况，这反映了胎儿的宫内情况 暴露与后代肥胖风险相关，但仍远未完全了解产前规划 对后代肥胖的治疗。新兴的代谢组学技术--一种系统的低分子质量图谱 生物体液和组织中的代谢物，提供了正在进行的生理过程以及外部 暴露在环境中。因此，产前代谢组学图谱将有可能代表生物学 内源性和外源性因素的过程，为产前提供生物学机制 用于预测儿童疾病发展的后代健康和早期生物标记物的规划。然而， 儿童肥胖的产前代谢谱研究，特别是纵向谱结合 对怀孕期间多个时间点的测量仍然很少。建议的总体目标是 这项研究旨在确定与儿童早期发育有关的产前循环代谢谱。 子代超重/肥胖风险的轨迹及其与代谢特征的关系 脐带血(用于机理研究)和产前可改变的危险因素(用于干预方法 调查)。这项拟议的研究将利用一大批当代双胞胎出生的婴儿重复进行 孕妇在怀孕期间采集血液，出生时采集脐带血，每年进行人体测量 对出生至4岁的儿童进行测量。共有1,425名(953名黑人和472名白人)母婴 配对将包括在这项研究中。基于LC-MS的两级液-质联用 代谢组学方法，包括相对量化的非目标分析(用于发现)，随后是 将使用以发现为导向的目标LC-MS分析和绝对量化(用于验证)来实现 具体目标：目标1)确定妊娠期特定变化和母体变化 孕期代谢谱与儿童早期生长轨迹和 4岁时的超重/肥胖风险；目的2)检查儿童结局相关的 Aim 1中确定的产前代谢组谱和脐带血的代谢组谱；Aim 3)检查 产前可改变的危险因素(如孕期体重增加、饮食和吸烟)与 目标1中确定的与儿童结局相关的产前代谢组谱。该项目将是第一个研究 目的：确定与儿童早期发育结果相关的产前纵向代谢谱。会的 为儿童肥胖和潜在的产前规划的生物学机制提供了新的线索 提供个性化的干预方法，以遏制美国儿童肥胖带来的巨大公共健康负担。

Childhood obesity remains one of the most serious public health challenges because of its persistent high prevalence and adverse health consequences. There is an urgent need for novel biomarkers which can predict and provide effective interventional targets for the early prevention of childhood obesity. Although a growing body of evidence strongly supports maternal conditions during pregnancy which reflect fetal intrauterine exposures are associated with obesity risk in offspring, it is still far from fully understanding prenatal programming for offspring obesity. The emerging metabolomics technology, a systematic profiling of low-molecular-weight metabolites in biofluids and tissues, provides a snapshot of ongoing physiological processes as well as external environmental exposures. Thus, prenatal metabolomics profiling will have the potential to represent biological processes of both endogenous and exogenous factors, providing biological mechanisms underlying prenatal programming of offspring health and early biomarkers for predicting child disease development. However, studies of prenatal metabolomic profiling for child obesity, especially longitudinal profiling which integrates measurements from multiple time points during pregnancy, are still scarce. The overall goal of the proposed study is to identify prenatal circulating metabolomic profiles which are associated with early childhood growth trajectories and overweight/obesity risk in offspring and to examine their associations with metabolomic profiles of cord blood (for mechanism investigation) and prenatal modifiable risk factors (for intervention method investigation). The proposed study will leverage a large and biracial contemporary birth cohort with repeated blood collection from the mothers during pregnancy, cord blood collection at birth, and annual anthropometric measurements of the children from birth to 4 years old. A total of 1,425 (953 black and 472 white) mother-child pairs will be included in this study. A two-stage liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach, including an untargeted analysis with relative quantification (for discovery), followed by a finding-driven targeted LC-MS analysis with absolute quantification (for validation) will be used to achieve the Specific Aims: Aim 1) To identify both gestation stage-specific and longitudinal changes in maternal metabolomic profiles during pregnancy which are associated with early childhood growth trajectories and overweight/obesity risk at age 4; Aim 2) To examine the associations between the childhood outcome-related prenatal metabolomic profiles identified in Aim 1 and the metabolomic profiles of cord blood; Aim 3) To examine the associations between prenatal modifiable risk factors (e.g., gestational weight gain, diet, and smoking) and the childhood outcome-related prenatal metabolomic profiles identified in Aim 1. This project will be the first study to identify prenatal longitudinal metabolomic profiles associated with early childhood growth outcomes. It will shed new light on the biological mechanisms of prenatal programming of childhood obesity and potentially provide personalized intervention methods to curb the huge public health burden of childhood obesity in the US.