Effect of Early-Life Exposure to Metal Mixtures on Lung Function and Mitochondrial DNA in Children

生命早期接触金属混合物对儿童肺功能和线粒体 DNA 的影响

• 批准号: 10609404
• 负责人: Muhammad F Parvez
• 金额: $ 54.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-02 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609404
• 关键词: Adult; Affect; Age; Animals; Arsenic; Bangladesh; Biological; Biological Markers; Biosensor; Blood; Bronchodilator Agents; Cadmium; Child; Child Health; Childhood; Collection; Data; Data Correlations; Development; Disease; Elderly; Environmental Pollutants; Exposure to; Goals; Health; Health Policy; Human; Impairment; Individual; Infrastructure; Intervention; Lead; Life; Link; Longitudinal Studies; Lung; Lung diseases; Manganese; Measurable; Measurement; Measures; Mediating; Mediation; Metal exposure; Metals; Methods; Mitochondria; Mitochondrial DNA; Modeling; Outcome; Oxidative Stress; Physiological; Predisposition; Pregnancy; Pregnant Women; Process; Property; Prospective cohort; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Research; Risk; Risk Factors; Sampling; Structure; Superfund; Time; Tooth structure; Toxic effect; Trees; Universities; Vital capacity; aged; blood-based biomarker; capsule; cost; cost efficient; deciduous tooth; early childhood; early life exposure; global health; improved; in utero; innovation; lung development; metal poisoning; mitochondrial DNA alteration; mitochondrial dysfunction; novel; oxidation; oxidative DNA damage; oxidative damage; prenatal; programs; pulmonary function; repaired; response; statistics; time use; tool; toxic metal

PROJECT SUMMARY Exposure to harmful toxic metals in utero and during early life is a global health problem. Although millions of children worldwide are exposed to multiple metals at those times, we still lack convincing evidence of the impact of metal exposure, particularly mixtures of metals, on childhood lung function. Indeed, most studies investigated metals individually, but in real life, pregnant women and their children are exposed to many metals simultaneously, and their combined effects are often unpredictable. Because the human lung develops through a sequence of highly choreographed processes, ideally, human studies would continuously measure levels of multiple metals to identify relevant windows of susceptibility. In this study, we will obtain weekly measurements of multiple metal exposures simultaneously by using a highly innovative method to measure metal levels in deciduous teeth. Like trees, teeth develop in layers that trap metals at concentrations commensurate with exposure levels. Hence, each layer is like a time capsule that contains metal levels from the time it was formed. We will use a validated method to measure 14 metals in teeth. We can assess exposures cumulatively, as well as at discrete week-by-week developmental windows, starting prenatally as early as gestational weeks 13-16 up to the time of tooth collection (~6 years). In order to develop a noninvasive and inexpensive biomarker for later-life lung function, we will combine our analyses of these metal assessments in teeth with novel blood-based biomarkers that leverage the unique properties of the mitochondrial DNA (mtDNA), a cumulative biosensor of metal-induced oxidative DNA damage. Our goal is to use tooth-based, time-specific measures of metals to assess their effects on lung function individually or as a mixture. We hypothesize that metals adversely affect lung function and that the effects of metal exposures on children’s lungs are associated with the cumulative damage measured in blood mtDNA. We can time- and cost-effectively conduct this research by leveraging the infrastructure of the Health Effects of Arsenic Longitudinal Study (HEALS), a well-characterized prospective cohort of 35,000 adults and their children in Araihazar, Bangladesh. The proposed study will include 600 children ages 6-10 years. We will collect at least one deciduous tooth sample from each child and conduct standard lung function tests and obtain blood mtDNA measures twice, 2 years apart. We anticipate that findings from this innovative and cost-efficient study will generate information on the impact of in utero and early-life exposure to multiple metals on pulmonary function in children. Information generated from this study will appreciably improve our understanding of lung function in response to environmental metal exposure and ultimately will inform strategies to improve lung function in children.

项目概要 在子宫内和生命早期接触有害的有毒金属是一个全球性的健康问题。尽管数百万 尽管当时世界各地的儿童都会接触多种金属，但我们仍然缺乏令人信服的证据 金属接触，特别是金属混合物，对儿童肺功能的影响。确实，大多数研究 单独研究金属，但在现实生活中，孕妇及其孩子会接触许多金属 同时，它们的综合影响往往是不可预测的。因为人的肺是通过 理想情况下，人类研究将持续测量一系列高度精心设计的过程 多种金属以确定相关的敏感性窗口。 在本研究中，我们将通过使用以下方法同时获得多种金属暴露的每周测量值 一种测量乳牙金属水平的高度创新方法。像树木一样，牙齿是分层发育的 以与暴露水平相当的浓度捕获金属。因此，每一层就像一个时间胶囊 自形成之日起就含有金属含量。我们将使用经过验证的方法来测量 14 种金属 牙齿。我们可以累积地评估暴露情况，也可以在离散的每周发育窗口评估暴露情况， 最早从妊娠第 13-16 周开始，一直到收集牙齿时（约 6 岁）。为了 为了开发一种用于晚年肺功能的无创且廉价的生物标志物，我们将结合我们的分析 利用新型血液生物标记物对牙齿进行金属评估，这些生物标记物利用了牙齿的独特特性 线粒体 DNA (mtDNA)，金属诱导的氧化 DNA 损伤的累积生物传感器。我们的目标是 使用基于牙齿的、特定时间的金属测量来单独或作为整体评估其对肺功能的影响 混合物。我们假设金属会对肺功能产生不利影响，并且金属暴露对肺功能的影响 儿童的肺部与血液线粒体 DNA 中测得的累积损伤有关。 我们可以利用卫生部门的基础设施，以时间和成本有效的方式开展这项研究 砷效应纵向研究 (HEALS)，这是一个由 35,000 名成年人和 他们的孩子在孟加拉国阿赖哈扎尔。拟议的研究将包括 600 名 6 至 10 岁的儿童。我们将 从每个孩子身上采集至少一份乳牙样本并进行标准肺功能测试 两次测量血液 mtDNA，间隔 2 年。 我们预计这项创新且具有成本效益的研究结果将产生有关 子宫内和生命早期接触多种金属对儿童肺功能的影响。信息 这项研究产生的结果将显着提高我们对肺功能的理解 环境金属暴露最终将为改善儿童肺功能的策略提供信息。