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以及肥胖风险的影响。肥胖是我们国家面临的最重要的健康问题之一。个体层面的根本原因以及人口快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生命的子宫内时期，此时在发育过程中暴露于次优条件可能会导致胎儿生理系统的编程，从而增加儿童和成年时期肥胖的风险。绝大多数关于胎儿肥胖规划的人类流行病学研究都依赖于出生时体型（例如低出生体重或小于胎龄出生）或胎儿和出生后早期生长速度的测量，作为不良宫内暴露的标志。我们提出了胎儿编程范式的创新和新颖应用，强调使用一组与压力相关的宫内母体-胎盘-胎儿（MPF）生物过程作为暴露于宫内侮辱的主要标志，因为MPF生物压力参数可以充当宫内环境质量的“传感器”以及其对发育中的影响的“传感器”。 胎儿以及随后的儿童和成人肥胖风险。我们研究中解决的具体问题包括以下内容：（1）在考虑了其他已确定的肥胖风险因素的影响后，人类妊娠期间产前压力暴露的 MPF 指数是否可以预测新生儿的身体成分以及从出生到 6 个月大的身体成分变化？ (2) 妊娠期间是否存在敏感期，此时发育中的胎儿特别容易受到产前生物应激对身体成分的影响？ (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出生后早期生长测量更具体、更敏感地预测新生儿和婴儿的身体成分？ (4) 强积金内分泌/免疫相关的身体成分变化对代谢功能（胰岛素敏感性）有何影响？ (5) 产前生物应激对身体成分的影响是否是通过能量平衡稳态设定点和能量通量随时间的变化而介导的？我们建议对参与 NIH 资助的妊娠期生物和行为过程研究的母亲所生婴儿进行一项前瞻性、纵向、后续研究。我们将对这个婴儿队列在其宫内生活和出生过程中进行广泛的描述，并采取解决上述问题所需的所有产前措施，包括母体-胎盘-胎儿内分泌和免疫/炎症环境的系列测量、基于超声的胎儿生物测量的系列测量、产科并发症的临床测量、母亲生物物理、社会人口统计学、行为、 心理社会特征和出生表型的测量。我们将从这个队列中招募 120-140 名出生儿童作为样本，并对他们进行跟踪直至 6 个月大。我们建议在 T1=0-2 周龄和 T2=6 个月龄时进行两项主要研究评估。每次评估时，我们的主要研究结果（儿童身体成分）将通过双能 X 射线吸收测定法 (DXA) 进行量化；总能量消耗（TEE）将使用双标记水（DLW）方法进行量化；代谢功能（胰岛素敏感性）将通过血糖和胰岛素的测量来量化。将使用多次 24 小时饮食召回来同时评估婴儿营养和喂养方法。将使用最先进的参数和非参数重复测量统计建模技术、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）来实现研究目标。这项研究的意义和影响源于更好地了解肥胖易感性增加的根本原因的重要性，从而为开发新的标记物以早期识别风险和干预目标提供信息。 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。多项研究表明，肥胖及其后遗症的起源可以追溯到生命的子宫内时期，此时在发育过程中暴露于次优条件可能会导致胎儿生理系统的编程，从而增加个体在儿童期和成年期肥胖的风险。关于这一过程背后的机制的几个关键问题仍有待回答。我们提出的研究的主要目标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以及肥胖风险的影响。通过使用已知可反映各种可能的宫内扰动的生物（母体-胎盘-胎儿内分泌和免疫）应激测量，我们认为，与主要关注出生时体型或母亲怀孕期间营养不足或营养过剩的其他研究相比，我们的方法将更有效地捕捉胎儿暴露于更广泛因素的情况。通过检查婴儿能量平衡随时间的变化，我们的研究将阐明暴露于不良宫内条件的影响背后的机制是否与生命早期这一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身体成分的宫内扰动相关变化对代谢功能的影响。因此，这项研究的科学意义在于，它将阐明个体易受子宫内压力相关肥胖结果影响的机制。对公共健康的影响是，从这项研究中获得的信息将有助于最终制定和测试干预措施所需的知识，以预防、最小化或扭转儿童因宫内生活中所经历的暴露而变得肥胖的风险，从而促进我们的孩子和子孙后代的健康。