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

儿童肥胖症由于其持续的高发病率，仍然是最严重的公共卫生挑战之一。 发病率和不良健康后果。迫切需要新的生物标志物，可以预测 为儿童肥胖的早期预防提供有效的干预靶点。尽管越来越 大量证据强烈支持妊娠期间的母体状况， 暴露与后代的肥胖风险有关，但还远未完全了解产前规划 对于后代肥胖症。新兴的代谢组学技术，一个系统的低分子量的分析， 生物流体和组织中的代谢物，提供了正在进行的生理过程以及外部 环境暴露。因此，产前代谢组学分析将有可能代表生物学特征， 过程的内源性和外源性因素，提供生物学机制的基础产前 规划后代健康和早期生物标志物以预测儿童疾病发展。然而，在这方面， 儿童肥胖症的产前代谢组学分析研究，特别是纵向分析， 在怀孕期间多个时间点的测量仍然很少。拟议的总体目标 一项研究旨在确定与儿童早期生长相关的产前循环代谢组学特征 轨迹和后代超重/肥胖风险，并检查其与代谢组学特征的相关性 脐带血（用于机制研究）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个大型的、双向的当代出生队列， 在怀孕期间从母亲采集血液，在出生时采集脐带血， 从出生到4岁的儿童的测量。共有1 425名（953名黑人和472名白色）母子 本研究将包括对。两阶段液相色谱-质谱（LC-MS） 代谢组学方法，包括相对定量的非靶向分析（用于发现），然后 将使用具有绝对定量（用于验证）的结果驱动的靶向LC-MS分析来实现 具体目的：目的1）确定母体妊娠期特异性和纵向变化， 怀孕期间的代谢组学特征与儿童早期生长轨迹相关， 4岁时的超重/肥胖风险;目的2）检查儿童结局相关的 目的1中确定的产前代谢组学谱和脐带血代谢组学谱;目的3）检查 产前可改变的风险因素（例如，妊娠期体重增加、饮食和吸烟）， 目标1中确定的与儿童结局相关的产前代谢组学特征。该项目将是第一个研究 以确定与儿童早期生长结果相关的产前纵向代谢谱。它将 揭示了儿童肥胖产前规划的生物学机制， 提供个性化的干预方法，以遏制美国儿童肥胖的巨大公共卫生负担。

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.