Advancing use of hair and salivary cortisol in stress-asthma research

 描述（由申请人提供）：虽然将产前压力与儿童过敏和喘息联系起来的证据不断增加，但其潜在机制仍知之甚少。大部分来自动物研究的数据表明，压力通过破坏关键的调节系统影响胎儿发育，特别关注改变母体和婴儿的下丘脑-垂体-肾上腺（HPA）轴功能（以皮质醇产生为指标）。压力诱导的母亲HPA轴变化被认为部分通过母体激素的经胎盘传递（例如，皮质醇），这可能对孩子的HPA轴产生编程影响，从子宫内开始，并在出生后持续存在。HPA功能中断，无论是 母亲在产前或婴儿期，可能导致免疫变化，使儿童易患过敏或哮喘。因此，研究纳入HPA轴的措施，在产前和产后早期可能会提供深入了解产前压力引起的编程早期呼吸道疾病的机制。由于评估孕妇和婴儿皮质醇产生的独特挑战，证明动物中记录的编程机制是否在人类中运作更加困难。在应对慢性应激时，HPA轴可能以比正常稳态更高或更低的水平运作。然而，流行病学研究中评估HPA轴的最佳方法仍不清楚。研究在很大程度上依赖于需要重复测量的唾液皮质醇节律指数，例如，皮质醇觉醒反应、昼夜皮质醇斜率和日输出量（曲线下面积; AUC）。个体唾液样本反映了几分钟到几小时内皮质醇的产生;唾液AUC和斜率代表了几天内的暴露量。唾液皮质醇测量也会受到情绪状态、采样日的压力源和其他因素（例如，睡眠、体力活动）。一个综合措施的皮质醇水平从头发，这反映了水平在几个星期到几个月内，已被提出捕捉更长期的（类特质）功能的HPA轴。早期的证据表明，头发皮质醇可能是一个有效的措施HPA轴功能。虽然一次性头发样本提供了优势，但主要的限制是重复唾液采样提供的动态信息的损失。我们建议，由于这些方法挖掘到相关的HPA轴的特质样功能的不同方面，一个综合指数，将综合头发的措施和信息，从重复的唾液采样可能提供一个更好的指标的激素环境影响胎儿的免疫和肺部发育。这些分析将采用先进的统计方法来探索新的计算方法，用于表征孕妇和婴儿的慢性皮质醇产生，并评估在模拟压力引起的HPA功能变化时，它们是否优于更传统的汇总测量，以及考虑推导出的皮质醇生物标志物作为儿童呼吸/过敏结局的预测因子。这将是第一项将头发和唾液皮质醇作为产前压力影响的复合生物标志物的研究。

 DESCRIPTION (provided by applicant): While evidence linking prenatal stress to childhood allergy and wheeze continues to grow, underlying mechanisms remain poorly understood. Data largely from animal studies suggest that stress influences fetal development through disruption of key regulatory systems with particular focus on altered maternal and infant hypothalamic-pituitary-adrenal (HPA) axis functioning indexed by cortisol production. Stress-induced changes to the mother's HPA axis are thought to influence offspring risk in part through trans-placental passage of maternal hormones (e.g., cortisol) which may have programming effects on the child's HPA axis starting in utero and persisting after birth. Disrupted HPA functioning, either in mothers prenatally or in infants, may result in immune changes that predispose children to allergy or asthma. Thus, studies incorporating HPA axis measures in the prenatal and early postnatal period may provide insight into mechanisms involved in prenatal stress-elicited programming of early respiratory disease. Demonstrating whether the programming mechanism documented in animals is operating in humans has been more difficult due to unique challenges to assessing cortisol production in pregnant women and infants. In response to chronic stress, the HPA axis may operate at higher or lower levels than in normal homeostasis. Best methods for assessing the HPA axis in epidemiological studies remain unclear however. Research has relied largely on indices of salivary cortisol rhythms necessitating repeated measures, e.g., cortisol awakening response, diurnal cortisol slope, and daily output (area under the curve; AUC). Individual saliva samples reflect cortisol production over minutes to hours; salivary AUC and slope represent exposure over days. Salivary cortisol measures are also subject to situational variance due to mood states, stressors on sampling days, and other factors (e.g., sleep, physical activity). An integrated measure of cortisol levels from hair, which reflects level over weeks to months, has been proposed to capture more long term (trait-like) functioning of the HPA axis. Early evidence suggests that hair cortisol may be a valid measure of HPA axis functioning. While a one-time hair sample offers advantages, a major limitation is the loss of dynamic information provided with repeated saliva sampling. We propose that since these approaches tap into different aspects relevant to trait-like functioning of the HPA axis, a composite index incorporating both the integrated hair measure and information available from repeated saliva sampling may provide a better indicator of the hormonal milieu influencing fetal immune and lung development. These analyses will apply advanced statistical approaches to explore novel computational methods for characterizing chronic cortisol production in pregnant women and infants and assess whether they offer advantages over more conventional summary measures when modeling stress-elicited changes in HPA functioning as well as considering the derived cortisol biomarkers as predictors of child respiratory/allergic outcomes. This will be the first study to consider hair and salivary cortisol as a composite biomarker measure of prenatal stress effects.