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

 描述(由申请人提供)：尽管将产前应激与儿童过敏和喘息联系起来的证据继续增加，但潜在的机制仍然知之甚少。主要来自动物研究的数据表明，应激通过扰乱关键调节系统来影响胎儿发育，尤其是以皮质醇产生为指标的母婴下丘脑-垂体-肾上腺(HPA)轴功能的改变。压力引起的母亲HPA轴的变化被认为部分是通过母体激素(如皮质醇)通过胎盘通过母亲的HPA轴，这可能对孩子的HPA轴产生编程影响，从子宫开始并在出生后持续。HPA功能中断，或者在 母亲在产前或在婴儿时期，可能会导致免疫系统的变化，使儿童容易过敏或哮喘。因此，结合出生前和出生后早期的HPA轴测量的研究可能会提供对产前应激诱导的早期呼吸道疾病编程的机制的洞察。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起作用变得更加困难。作为对慢性应激的反应，HPA轴可能以高于或低于正常内稳态的水平运行。然而，在流行病学研究中评估HPA轴的最佳方法仍然不清楚。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，例如皮质醇唤醒反应、每日皮质醇斜率和每日输出量(曲线下面积；AUC)。个别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SLOPE代表了几天的暴露。唾液皮质醇测量也会因情绪状态、样本日的压力因素和其他因素(如睡眠、体力活动)而受到情境变化的影响。一种综合的测量头发皮质醇水平的方法被提出，它反映了几周到几个月的皮质醇水平，以捕捉HPA轴更长期的(类似特征的)功能。早期证据表明，头发皮质醇可能是HPA轴功能的有效衡量标准。虽然一次性头发样本提供了优势，但主要限制是重复唾液样本提供的动态信息的损失。我们认为，由于这些方法利用了与HPA轴的特征样功能相关的不同方面，综合毛发测量和重复唾液采样获得的信息的综合指数可能会更好地指示影响胎儿免疫和肺发育的激素环境。这些分析将应用先进的统计学方法，探索新的计算方法来表征孕妇和婴儿的慢性皮质醇产生，并评估它们在模拟压力引起的HPA功能变化以及考虑将衍生的皮质醇生物标记物作为儿童呼吸/过敏结果的预测因子时，是否比更传统的总结方法更具优势。这将是第一项将头发和唾液皮质醇作为产前应激影响的复合生物标记物的研究。

 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.