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

项目摘要 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。虽然数百万 尽管全世界的儿童在这些时候接触多种金属，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。事实上，大多数研究 我们对金属进行了单独的研究，但在真实的生活中，孕妇和她们的孩子会接触到许多金属 同时，它们的综合影响往往是不可预测的。因为人类的肺是通过 一系列高度编排的过程，理想情况下，人类研究将连续测量 多种金属，以确定敏感性的相关窗口。 在这项研究中，我们将获得每周测量的多种金属接触，同时使用 一种高度创新的方法来测量乳牙中的金属含量。像树一样，牙齿也是分层发育的， 捕获浓度与暴露水平相当的金属。因此，每一层都像一个时间胶囊， 从它形成的时候就含有金属元素我们将使用经过验证的方法测量14种金属， 牙齿.我们可以评估累积的暴露，以及在离散的逐周发育窗口， 早在妊娠第13-16周就开始产前检查，直至牙齿采集时（约6年）。为了 为了开发一种非侵入性和廉价的生物标志物，用于以后的肺功能，我们将联合收割机结合我们的分析， 这些牙齿中的金属评估与新的血液为基础的生物标志物，利用独特的性质， 线粒体DNA（mtDNA），金属诱导的氧化性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方法来评估它们对肺功能的影响， 混合物.我们假设金属会对肺功能产生不利影响， 儿童的肺部与血液mtDNA中测量的累积损伤有关。 我们可以通过利用卫生部的基础设施， 砷的纵向影响研究（HEALS），一项由35,000名成年人组成的前瞻性队列研究， 他们的孩子在孟加拉国的Araihazar。这项研究将包括600名6-10岁的儿童。我们将 从每个孩子身上收集至少一个乳牙样本，并进行标准肺功能测试， 每隔两年进行两次血液mtDNA检测。 我们预计，这项创新和具有成本效益的研究的结果将产生关于 宫内和生命早期暴露于多种金属对儿童肺功能影响信息 这项研究产生的结果将大大提高我们对肺功能的理解， 环境金属暴露，并最终将为改善儿童肺功能的策略提供信息。

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.