A Multisite Study of Prenatal Alcohol Exposure: Effects of Inflammation and Endocrine Dysfunction in Adulthood

尽管产前酒精暴露(PAE)对早期发育的影响已经得到很好的证实， 健康与疾病的发育起源(DOHAD)假说表明， 增加成人疾病或紊乱风险的长期后果。此前，这是一件困难的事情 在受影响的个体中，将PAE的影响与其他生活经历相关的影响隔离开来 通常，PAE的作用可能会被忽视。事实上，从这个背景来看，PAE可以被考虑 一系列不良暴露中的第一个，最终导致更高的负面结果风险 这些脆弱的人群。PAE对胎儿系统的编程可能会改变发育轨迹 并导致一种敏感的有机体，很容易受到以后生活的挑战。内分泌与免疫 人们已经发现，系统非常容易受到早期生活事件的编程的影响，这些系统一起被 被认为在将早期生活不良暴露与长期健康和功能联系起来方面发挥关键作用 结果。因此，这些系统的编程可能是PAE影响成年人的一种机制 健康和神经行为结果。在我们正在进行的CIFASD4研究中，PAE对 观察到中年的身体和心理健康结果，并将其归因于PAE和 与早年生活逆境和社会因素相关。还注意到长期的、不利的变化 免疫功能，炎症从婴儿期开始一直持续到成年，表明 增加了生命过程中的炎症负担。在这项拟议的研究中，我们将测试“多次命中”。 假设PAE导致脆弱的有机体，可能会进一步受到社会逆境的影响 以及缺乏资源/应对技能，导致免疫和内分泌失调，进而可能 生命过程中早发性健康和神经行为问题的关键驱动因素。360人 代表来自亚特兰大、西雅图和加拿大三个地点的不同受影响个人样本 参与中年PAE效应的准实验研究。除了测量PAE/FASD之外 和环境条件，我们将使用最先进的方法来识别生物标记物 炎症、血管生成、血管损伤、代谢和神经退行性标记物、转录 单个细胞的轮廓和端粒长度)的早发性功能缺陷，包括 和心理健康。具体地说，在社会逆境的负面影响和 社会资源和应对技能的积极影响，我们将评估：目标1.免疫和应对技能的作用 患有FASD/PAE的成年人的生理和心理健康结局中的内分泌失调；目标2 PAE的影响及PAE诱导的免疫和内分泌失调可能的作用 成人FASD/PAE患者的神经认知表现和早发性功能障碍标志物 与年龄匹配的对照组和健康的老年人进行比较。

Although the impact of prenatal alcohol exposure (PAE) on early development has been well established, the Developmental Origins of Health and Disease (DOHaD) hypothesis suggests there may be longer- term consequences that increase the risk for adult diseases or disorders. Previously, it has been difficult to isolate the effects of PAE from those associated with other life experiences in affected individuals so that, often, the role of PAE may be overlooked. In fact, viewed from this context, PAE may be considered the first in a series of adverse exposures that result, eventually, in a higher risk for negative outcomes in this vulnerable population. Programing of fetal systems by PAE may alter the developmental trajectory and result in a sensitized organism that is vulnerable to later life challenges. The endocrine and immune systems have been found to be highly susceptible to programming by early life events, and together are thought to play key roles in linking early life adverse exposures with long-term health and functional outcomes. Thus, programming of these systems may be one mechanism by which PAE impacts adult health and neurobehavioral outcomes. In our ongoing CIFASD4 research negative impacts of PAE on physical and mental health outcomes in midlife were observed and attributable to both PAE and to associated early life adversity and social factors. Also noted were long-lasting, adverse changes in immune function, with inflammation starting in infancy and lasting into adulthood, suggesting an increased inflammatory burden over the life course. In the proposed study, we will test a “multiple hit” hypothesis that PAE results in a vulnerable organism that may be further impacted by social adversity and lack of resources/coping skills, resulting in immune and endocrine dysregulation that in turn, may be key drivers of early-onset health and neurobehavioral problems over the life course. 360 individuals representing a diverse sample of affected individuals from three sites, Atlanta, Seattle, and Canada, will participate in a quasi-experimental study of PAE effects in midlife. In addition to measuring PAE/FASD and environmental conditions, we will use state-of-the-art methodologies to identify biomarkers (inflammatory, angiogenesis, vascular injury, metabolic, and neurodegenerative markers, transcriptional profiling of individual cells, and telomere length) of early-onset functional deficits including both physical and mental health. Specifically, within the context of the negative effects of social adversity and the positive influences of social resources and coping skills, we will evaluate: Aim 1. the role of immune and endocrine dysregulation in physical and mental health outcomes in adults with FASD/PAE; Aim 2 the impact of PAE and the possible role of PAE-induced immune and endocrine dysregulation on neurocognitive performance and markers of early-onset functional deficits in adults with FASD/PAE in comparison to age-matched controls and healthy older individuals.