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: 10332729
• 负责人: Marc G Weisskopf
• 金额: $ 46.41万
• 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/10332729
• 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.

项目概要/摘要 我们建议研究产前和产后早期接触金属以及金属 成年期的接触量——老年时的认知功能，以及生命早期接触金属的程度 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) 的变化有关，这可能 代表关联背后的表观遗传机制。我们将对一部分人进行队列研究 最初的圣路易斯乳牙 (SLBT) 研究的参与者在 20 世纪 50 年代捐赠了乳牙， 20 世纪 60 年代。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 男性和 500 名女性），我们将从他们身上采集血液和脚趾甲样本，所有人都会做出反应 进行问卷调查并进行认知测试。产前和产后早期暴露于 1,000 至数个 将通过测量乳牙釉质中的金属来评估金属（使用激光烧蚀感应耦合技术） 等离子体质谱法）。将通过分析一系列剪下的脚趾甲来评估成人的金属暴露情况 大约每年收集一次。将从血液样本中分离出 EV 并分析 EV miRNA 表达水平。 SLBT 提供了一个独特的设置，使我们能够拥有个体水平的生物标志物 我们可以对老年人的早期金属暴露进行认知功能测试。本研究设置 使我们拥有前所未有的能力来检查早期生活暴露是否与晚年相关 认知健康——动物研究提出的假设，但如果没有认知健康，就很难在人类身上进行测试 SLBT 中已收集的乳牙可以提供这种早期暴露的生物标志物。