Metals, critical windows of exposures, epigenetics, and late life cognitive function

金属、关键暴露窗口、表观遗传学和晚年认知功能

• 批准号: 10112924
• 负责人: Marc G Weisskopf
• 金额: $ 42.99万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112924
• 关键词: Ablation; Accounting; Address; Adult; Age; Alzheimer' s Disease; American; Animal Experimentation; Animals; Biological; Biological Markers; Blood; Blood specimen; Cells; Child; Cognitive; Cognitive aging; Cohort Studies; Data; Dementia; Dental Enamel; Deposition; Disease; Economic Burden; Elderly; Encapsulated; Enrollment; Environmental Exposure; Epigenetic Process; Exposure to; Gene Expression; Genetic Transcription; Health; Home; Human; Impaired cognition; Individual; Inductively Coupled Plasma Mass Spectrometry; Industrialization; Intervention; Lasers; Lead; Life; Link; Lipid Bilayers; Measures; Metal exposure; Metals; MicroRNAs; Modification; Neurons; Outcome; Participant; Pathology; Patients; Performance; Population; Public Health; Questionnaires; Research; Risk; Risk Factors; Role; Sampling; Series; Serum; Signal Transduction; Site; Source; Structure of nail of toe; Superfund; Testing; Therapeutic; Time; Tooth structure; United States; Woman; Work; age related; aging brain; aging population; base; cognitive development; cognitive function; cognitive testing; cost estimate; early childhood; early detection biomarkers; early life exposure; economic cost; extracellular vesicles; human study; in utero; lead exposure; men; nanoscale; novel marker; particle; postnatal; prenatal; recruit; remediation; superfund site; water sampling

PROJECT SUMMARY/ABSTRACT We propose to study the relation between prenatal and early postnatal exposure to metals—as well as metal exposures in adulthood—and cognitive function in older age, and the extent to which early life metal exposures modify the 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) from whom we will collect blood and toenail samples, and all of whom will have responded to questionnaires and undergone cognitive testing. Prenatal and early postnatal exposure of the 1,000 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 by analyzing a series of toenail clippings collected roughly once a year. 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 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 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.

项目总结/摘要 我们建议研究产前和产后早期接触金属的关系， 暴露在成年和认知功能在老年，以及在何种程度上， 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 与血液来源的细胞外囊泡（EV）微小RNA表达（miRNA）的变化相关， 代表了关联背后的表观遗传机制。我们将在以下人群中进行队列研究： 圣路易斯婴儿牙齿（SLBT）研究的参与者在20世纪50年代捐赠了他们的婴儿牙齿， 60年代根据我们的试点工作，我们预计可以轻松招募1，000名前SLBT参与者（500名 男性和500名女性），我们将收集他们的血液和脚趾甲样本，所有这些人都将作出反应， 进行问卷调查和认知测试。1，000至几个月的产前和产后早期接触 金属将通过测量乳牙釉质中的金属（使用激光消融感应耦合 等离子体质谱法）。成人金属暴露将通过分析一系列脚趾甲剪下的评估 大约每年收集一次。将从血液样本中分离EV并分析EV miRNA 表达水平。SLBT提供了一个独特的环境，使我们能够获得以下个体水平的生物标志物： 我们可以对老年人进行认知功能测试。本研究设置 使我们有了前所未有的能力来检查早期生活暴露是否与晚年生活有关 认知健康--这是一个从动物研究中提出的假设，但如果没有 SLBT中已经收集的乳牙可以提供这种早期暴露的生物标志物。