Metals and Developmental Origins of Late Life Cognitive Function

我们建议研究出生前、出生后早期和成人接触金属和 老年人的认知功能，以及早期生活暴露是否会改变成人暴露的影响。我们还将 探讨这些暴露和认知结果是否与血液来源的变化有关 细胞外小泡(EV)微小RNA表达(MiRNA)，这可能代表表观遗传机制 潜在的关联。我们将在最初的圣路易斯的参与者中进行一项队列研究 20世纪50年代和60年代捐赠乳牙的婴儿牙齿(SLBT)研究。根据我们的试点工作，我们 预计能够轻松招募1,000名前SLBT参与者(500名男性和500名女性)，他们将拥有 完成了问卷调查和认知功能测试，我们将从谁那里采集血液进行miRNA 成人金属分析和重复脚趾甲样本。出生前和出生后早期暴露于 将通过测量乳牙釉质中的金属(使用激光感应消融)来评估几种金属 耦合等离子体质谱)。将使用X射线荧光来评估成人金属暴露 测量脚趾甲样本中的金属。将从血液样本中分离出EV并进行EV分析 MiRNA表达水平。SLBT提供了一个独特的设置，使我们能够拥有个人级别的 老年人早期生活和成人金属暴露的生物标记物，我们可以对其进行认知功能测试 测试。这项研究让我们有了前所未有的能力来检查早期生命暴露 与晚年认知健康有关--这是动物研究中对金属暴露提出的假设，但 在没有如此早期接触的生物标志物的情况下，在人类身上进行测试极其困难，因为已经收集的婴儿 SLBT中的牙齿可以提供。

We propose to study the relation between prenatal, early postnatal, and adult exposure to metals and cognitive function in older age, and whether early life exposures modify effects of adult exposures. We will also explore whether those exposures and cognitive outcomes are associated with changes in blood-derived extracellular vesicle (EV) micro RNA expression (miRNA), which could represent epigenetic mechanisms underlying associations. We will conduct a cohort study among a subset of participants in the original St. Louis Baby Tooth (SLBT) study who donated their baby teeth in the 1950s and 1960s. Based on our pilot work, we anticipate easily being able to enroll 1,000 former SLBT participants (500 men and 500 women) who will have completed questionnaires and cognitive function testing, and from whom we will collect blood for miRNA analyses and repeated toenail samples for adult metal analyses. Prenatal and early postnatal exposure to several metals will be assessed by measuring metals in baby tooth enamel (using laser-ablation inductively coupled plasma mass spectrometry). Adult metal exposures will be assessed using X-Ray Fluorescence to measure metals in the toenail samples. EVs will be isolated from the blood samples and analyzed for EV miRNA expression levels. The SLBT provides a unique setting that will allow us to have individual-level biomarkers of early life and adult metal exposures in older adults on whom we can conduct cognitive function testing. This study setting allows us to have an unprecedented ability to examine whether early life exposures are related to late life cognitive health—a hypothesis suggested for metals exposure from animal research, but extremely hard to test in humans without the biomarker of such early exposure that the already collected baby teeth in the SLBT can provide.