Prenatal stress biology, infant body composition and obesity risk

产前应激生物学、婴儿身体成分和肥胖风险

• 批准号: 8112558
• 负责人: Sonja Entringer
• 金额: $ 41.47万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112558
• 关键词: Accounting; Address; Adult; Age; Age-Months; Animals; Area; Back; Behavioral; Biological; Biological Process; Biology; Biometry; Birth; Birth Rate; Blood Glucose; Body Composition; Bottle feeding; Breast; California; Cardiovascular system; Caregivers; Cell Proliferation; Cells; Characteristics; Child; Childhood; Classification; Clinical; Corticotropin-Releasing Hormone; Cost Savings; Coupling; Data; Data Element; Development; Diet; Discipline of obstetrics; Disease; Early identification; Endocrine; Energy Intake; Energy Metabolism; Environment; Epidemiologic Studies; Epidemiology; Equilibrium; Expenditure; Exposure to; Fatty acid glycerol esters; Fetal Development; Fetal Growth; Fetus; First Pregnancy Trimester; Funding; Future Generations; Genetic; Genetic Variation; Gestational Age; Glucocorticoids; Glucose; Goals; Growth; Health; Homeostasis; Human; Hydrocortisone; Immune; Individual; Individual Differences; Infant; Inflammatory; Insulin; Interleukin-6; Intervention; Interview; Knowledge; Label; Life; Live Birth; Long-Term Effects; Longitudinal Studies; Low Birth Weight Infant; Maintenance; Malnutrition; Maternal Behavior; Measures; Mediating; Mediator of activation protein; Medicine; Metabolic; Methods; Modeling; Modification; Molecular; Mothers; Newborn Infant; Nutritional; Obesity; Outcome; Outcome Study; Overnutrition; Parents; Pathway interactions; Perinatal Exposure; Peripheral; Phenotype; Physiological; Physiological Processes; Physiology; Play; Polynomial Models; Population; Positioning Attribute; Predisposition; Pregnancy; Process; Psychophysiology; Psychosocial Factor; Psychosocial Stress; Public Health; Recruitment Activity; Regression Analysis; Relative (related person); Reliance; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Second Pregnancy Trimester; Sensitivity and Specificity; Series; Signal Transduction; Small for Gestational Age Infant; Smoking; Staging; Statistical Models; Stress; Study Subject; System; Techniques; Testing; Third Pregnancy Trimester; Time; Tissues; Training; Transducers; Trees; Ultrasonography; United States National Institutes of Health; Universities; Variant; Vulnerable Populations; Water; Weight; Weight Gain; Work; adverse outcome; base; biobehavior; body system; cohort; college; critical period; cytokine; disorder risk; energy balance; experience; feeding; fetal; fetal programming; follow-up; glycemic control; improved; in utero; indexing; infant nutrition; infant outcome; inflammatory marker; innovation; insulin sensitivity; interest; maternal stress; mother nutrition; novel; novel marker; novel strategies; obesity in children; obesity risk; offspring; population based; postnatal; prenatal; prenatal stress; prevent; programs; prospective; psychosocial; public health relevance; relating to nervous system; sensor; sex; stressor

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. PUBLIC HEALTH RELEVANCE: This proposal addresses one of the most important public health issues in our nation - the problem of childhood obesity. Several studies suggest the origins of obesity and its sequelae can be traced back to the intrauterine period of life, at which time exposure to suboptimal conditions during development may result in fetal programming of physiological systems that confer increased risk in that individual for becoming obese in childhood and adult life. Several key questions still remain to be answered about the mechanisms underlying this process. The main goal of our proposed study is to examine the influence of adverse intrauterine conditions, or prenatal stress, on newborn and infant body composition and obesity risk. By using biological (maternal-placental- fetal endocrine and immune) stress measures that are known to reflect a variety of possible intrauterine perturbations, we suggest our approach will be more effective in capturing fetal exposure to a broader set of factors than other studies that have focused primarily on size at birth or maternal under- or overnutrition during pregnancy. By examining changes in infant energy balance over time, our study will clarify whether the mechanisms that underlie the effects of exposure to adverse intrauterine conditions relate to alterations of this particularly important regulatory processes in early life. By concurrently assessing infant insulin sensitivity, we will be able to study the consequences of intrauterine perturbation-related changes in newborn and infant body composition on metabolic function. Thus, the scientific significance of this research is that it will clarify the mechanisms that underlie individual vulnerability for in utero stress-related obesity outcomes. The public health impact is that the information gained from this study will contribute knowledge that is required to ultimately develop and test interventions to prevent, minimize or reverse the risk of a child becoming obese as a consequence of the exposures she or he experienced during intrauterine life, and thereby promote better health for our children and future generations.

描述（由申请人提供）：我们的研究的目的是检查不良宫内条件或产前压力的影响，对新生儿和婴儿的组成和肥胖风险。肥胖是我们国家面临的最重要的健康问题之一。在个人层面上的基本原因，以及人口迅速增加的原因并没有得到充分理解。有证据表明，肥胖及其后遗症的起源可以追溯到生命的内在时期，此时在发育过程中暴露于次优条件可能会导致生理系统的胎儿编程，然后赋予儿童和成人生活中肥胖风险的增加。肥胖胎儿编程的绝大多数人流行病学研究都依赖于出生时大小（例如低出生体重或小胎龄出生），或胎儿和早期产后生长速度的措施，作为不良内渗渗渗；我们通过强调使用一组与压力相关的宫内孕产妇（MPF）生物学过程的使用，提出了胎儿编程范式的创新和新颖应用，因为MPF生物学参数可能会作为质量的环境，因为MPF生物压力参数可以作为质量的环境效果，因此，在宫内内侮辱的主要标志是属于宫内的侮辱。胎儿和随后的童年和成人肥胖风险。我们研究中解决的具体问题包括以下内容：（1）在人妊娠的产前压力暴露的MPF指数是否可以预测新生体的组成和身体成分从出生到6个月的变化，在考虑了其他既定风险因素对肥胖的影响之后？ （2）妊娠期间是否有敏感时期，发育中的胎儿特别容易受到产前生物压力对人体组成的影响？ （3）与当前使用的出生结局或胎儿和早期产后生长的措施相比，新生儿和婴儿身体组成的宫内环境的MPF生物压力度量是否更具体和敏感的预测因素？ （4）MPF内分泌/免疫相关的人体组成变化对代谢功能（胰岛素敏感性）有何影响？ （5）产前生物学应激对通过能量平衡稳态设定点和能量通量随时间变化而介导的人体组成的影响？我们建议在母亲出生的基于人群的婴儿中进行一项前瞻性，纵向的后续研究，这些婴儿将参加NIH资助的对怀孕的生物学和行为过程的研究。我们将在这个婴儿队列的过程中具有广泛的特征，并在他们的宫内寿命和出生过程中，以及解决上述问题所需的所有产前措施，包括对孕产妇 - 置换胎儿内分泌和免疫/炎症环境的序列措施，对胎儿生物识别的基于胎儿生物含量的临床措施，对胎儿生物统计学的衡量，对胎儿生物序列的衡量，属于胎儿的措施，衡量了胎儿，，衡量了术语，衡量了术语，衡量了术语，衡量了术语，衡量了术语，衡量了胎儿，衡量了胎儿，，是针对性的，是胎儿的。心理特征和出生表型的度量。从这个队列中，我们将在出生时招募120-140名儿童的样本，并跟随他们直至6个月大。我们提出了T1 = 0-2周的两项主要研究评估，T2 = 6个月大。在每次评估中，我们的主要研究结果，儿童身体组成，将通过双能X射线吸收法（DXA）来量化；总能量支出（TEE）将使用双重标记的水（DLW）方法进行量化；将从血糖和胰岛素的测量中量化代谢功能（胰岛素敏感性）。婴儿营养和喂养实践将使用多通饮食召回来同时评估。针对参数和非参数重复测量的最先进的统计建模技术，时间序列数据，包括通用加性模型，多项式分布式滞后，分类和回归树以及多变量回归分析，用于解决研究目标。这项研究的重要性和影响来自于更好地理解增加肥胖症易感性的基本原因的重要性，从而为早期识别风险和干预目标的新标记提供了开发。 公共卫生相关性：该提案解决了我们国家最重要的公共卫生问题之一 - 儿童肥胖问题。几项研究表明，肥胖及其后遗症的起源可以追溯到生命的宫内，此时在发育过程中暴露于次优条件可能会导致生理系统的胎儿编程，从而赋予该人在儿童期和成人生活中肥胖的风险增加。关于此过程的基础机制，仍然有几个关键问题要回答。我们拟议的研究的主要目标是检查不良宫内疾病或产前压力对新生儿和婴儿身体组成和肥胖风险的影响。通过使用生物学（孕产妇 - 胎儿内分泌和免疫）应力度量，这些措施反映了各种可能的子宫内扰动，我们建议我们的方法在捕获胎儿暴露于胎儿中比其他主要集中在出生时大小或孕妇在怀孕期间的胎儿大小或养分型的研究更有效。通过检查婴儿能量平衡的变化，我们的研究将阐明暴露于不良宫内条件的影响的机制是否与早期生活中这种特别重要的调节过程的改变有关。通过同时评估婴儿胰岛素敏感性，我们将能够研究新生儿和婴儿体组成对代谢功能的宫内扰动相关变化的后果。因此，这项研究的科学意义在于，它将阐明与子宫应激相关肥胖结果中个人脆弱性的基础的机制。公共卫生的影响是，从这项研究中获得的信息将有助于最终开发和测试干预措施，以防止，最小化或扭转由于他或他在子宫内生活中经历的暴露，从而最大程度地降低或扭转孩子肥胖的风险，从而促进我们孩子和子孙后代更好的健康。