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

项目总结 在宫内和生命早期接触有害有毒金属是一个全球健康问题。尽管数百万人 尽管世界各地的儿童在那个时候接触了多种金属，但我们仍然缺乏令人信服的证据来证明 接触金属，特别是混合金属对儿童肺功能的影响。事实上，大多数研究 单独调查金属，但在现实生活中，孕妇和她们的孩子接触到许多金属 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 一系列精心设计的过程，理想情况下，人体研究将持续测量 多种金属，以确定相关的易感窗口。 在这项研究中，我们将通过使用以下方法同时获得多个金属暴露的每周测量数据 一种高度创新的方法来测量乳牙中的金属水平。就像树一样，牙齿是层层生长的 在与暴露水平相称的浓度下捕获金属。因此，每一层都像一个时间胶囊， 从它形成的时候起就包含了金属水平。我们将使用一种经过验证的方法测量14种金属 牙。我们可以累积地评估暴露，也可以在每周不连续的发育窗口评估暴露， 从孕13-16周开始产前至拔牙时(~6岁)。为了 开发一种非侵入性和廉价的生物标记物用于以后的肺功能，我们将结合我们对 这些金属评估在牙齿中具有新的基于血液的生物标记物，利用 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方法来单独或作为评估其对肺功能的影响 混合物。我们假设，金属对肺功能有不利影响，金属暴露对肺功能的影响 儿童的肺与血液mtDNA测量的累积损伤有关。 通过利用Health的基础设施，我们可以在时间和成本效益上进行这项研究 砷纵向研究(HeALS)的影响，一个具有良好特征的3.5万名成年人和 他们的孩子在孟加拉国的阿拉伊哈扎尔。这项拟议的研究将包括600名6-10岁的儿童。我们会 从每个儿童身上收集至少一个乳牙样本，并进行标准的肺功能测试和 两次采血测线粒体DNA，相隔2年。 我们预计，这项创新和具有成本效益的研究结果将产生关于 宫内和生命早期接触多种金属对儿童肺功能的影响。信息 这项研究产生的数据将显著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参考。

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.