Prenatal stress biology, infant body composition and obesity risk

描述（由申请人提供）：我们研究的目的是检查不良宫内条件或产前压力对新生儿和婴儿身体成分和肥胖风险的影响。肥胖是我们国家面临的最重要的健康问题之一。在个人层面上的潜在原因，以及其人口迅速增长的原因尚不清楚。有证据表明，肥胖及其后遗症的起源可以追溯到子宫内的生命时期，在这个时期，发育过程中暴露于次优条件可能导致胎儿生理系统的编程，从而增加儿童和成年生活中肥胖的风险。绝大多数关于胎儿肥胖的人类流行病学研究都依赖于出生时的体型（如低出生体重或小于胎龄出生），或胎儿和产后早期的生长速度，作为不良宫内暴露的标志。我们通过强调使用一组与压力相关的宫内母-胎盘-胎儿（MPF）生物过程作为宫内损伤暴露的主要标记，提出了胎儿规划范式的创新和新颖应用，因为MPF生物应激参数可能作为宫内环境质量的“传感器”，以及其对发育中的胎儿和随后的儿童和成人肥胖风险的影响的“传感器”。在我们的研究中解决的具体问题包括：(1)在考虑了其他已知的肥胖危险因素的影响后，人类妊娠期产前应激暴露的MPF指数能否预测新生儿的身体成分以及从出生到6个月的身体成分变化？(2)妊娠期是否存在发育中的胎儿特别容易受到产前生物应激对机体成分影响的敏感期？(3)宫内环境的MPF生物应激测量是否比目前使用的出生结局或胎儿和产后早期生长的测量更具体和敏感地预测新生儿和婴儿的身体组成？(4)强积金中与内分泌/免疫有关的身体成分改变对代谢功能（胰岛素敏感性）有何影响？(5)产前生物应激对机体组成的影响是否通过能量平衡稳态设定点和能量通量随时间的变化介导？我们建议对参加美国国立卫生研究院资助的孕期生物学和行为过程研究的母亲所生的婴儿进行前瞻性、纵向、随访研究。我们将对这组婴儿在其宫内生活和出生过程中进行广泛的特征描述，并采用解决上述问题所需的所有产前测量，包括母体-胎盘-胎儿内分泌和免疫/炎症环境的系列测量，基于超声波的胎儿生物测量的系列测量，产科并发症的临床测量，产妇生物物理，社会人口统计学，行为，心理社会特征的测量，以及出生表现型的测量。从这个队列中，我们将招募120-140名出生时的儿童作为样本，并跟踪他们直到6个月大。我们建议在T1=0-2周和T2=6个月时进行两项主要研究评估。在每次评估中，我们的主要研究结果，儿童身体成分，将通过双能x射线吸收仪（DXA）进行量化；总能量消耗（TEE）将采用双标签水（DLW）法进行量化；代谢功能（胰岛素敏感性）将通过测量血糖和胰岛素来量化。婴儿营养和喂养方法将通过多次24小时饮食召回同时进行评估。最先进的统计建模技术用于参数和非参数重复测量，时间序列数据，包括广义加性模型，多项式分布滞后，分类和回归树，以及多元回归分析，将用于解决研究目标。这项研究的意义和影响来自于更好地理解肥胖易感性增加的潜在原因的重要性，从而为早期识别风险和干预目标的新标记的开发提供了信息。

DESCRIPTION (provided by applicant): The goal of our study is to examine the influence of adverse intrauterine conditions, or prenatal stress, on newborn and infant body composition and obesity risk. Obesity is one of the most important health issues facing our nation. The underlying causes at the individual level, and the reasons for its rapid increase in the population are not well-understood. Evidence suggests that the origins of obesity and its sequelae can be traced back to the intra-uterine period of life, at which time exposure to suboptimal conditions during development may result in fetal programming of physiological systems that then confer increased risk for obesity in childhood and adult life. The overwhelming majority of human epidemiological studies of fetal programming of obesity have relied on measures of either size at birth (such as low birth weight or small-for-gestational age birth), or fetal and early postnatal growth velocity, as markers of adverse intrauterine exposures. We propose an innovative and novel application of the fetal programming paradigm by emphasizing the use of a set of stress-related intrauterine maternal-placental-fetal (MPF) biological processes as the principal markers of exposure to intrauterine insult because MPF biological stress parameters may act as "sensors" of the quality of the intrauterine environment as well as "transducers" of its effects on the developing fetus and subsequent childhood and adult obesity risk. The specific questions addressed in our study include the following: (1) Do MPF indices of prenatal stress exposure over human gestation predict newborn body composition and change in body composition from birth until 6 months age, after accounting for the effects of other established risk factors for obesity? (2) Are there sensitive periods during gestation when the developing fetus is particularly vulnerable to the effects of prenatal biological stress on body composition? (3) Are MPF biological stress measures of the intrauterine environment more specific and sensitive predictors of newborn and infant body composition than currently-used measures of birth outcomes or fetal and early postnatal growth? (4) What are the consequences of MPF endocrine/immune-related changes in body composition on metabolic function (insulin sensitivity)? (5) Are the effects of prenatal biological stress on body composition mediated through a change in energy balance homeostasis set points and energy flux over time? We propose to conduct a prospective, longitudinal, follow-up study in a population-based cohort of infants born to mothers who will participate in a NIH-funded study of biological and behavioral processes in pregnancy. We will have extensive characterization in this infant cohort over the course of their intrauterine life and birth with all the prenatal measures required to address the above questions, including serial measures of the maternal-placental- fetal endocrine and immune/inflammatory milieu, serial ultrasound-based measures of fetal biometry, clinical measures of obstetric complications, measures of maternal biophysical, sociodemographic, behavioral, psychosocial characteristics, and measures of the birth phenotype. From this cohort we will recruit a sample of 120-140 children at birth and follow them up until 6 months age. We propose two major study assessments at T1=0-2 weeks and T2=6 months age. At each assessment our primary study outcome, child body composition, will be quantified by dual energy x-ray absorptiometry (DXA); total energy expenditure (TEE) will be quantified using the doubly labeled water (DLW) method; and metabolic function (insulin sensitivity) will be quantified from measures of blood glucose and insulin. Infant nutrition and feeding practices will be assessed concurrently using multiple-pass 24h diet recalls. State-of-the-art statistical modeling techniques for parametric and non-parametric repeated measures, time- series data, including generalized additive models, polynomial distributed lag, classification and regression trees, and multivariate regression analysis will be used to address the study aims. The significance and impact of this study derives from the importance of achieving at a better understanding of the underlying causes for increased susceptibility for obesity, thereby informing the development of new markers for early identification of risk and targets for intervention.