Effect of Perinatal Exposure to Metals on Lung Function Trajectories and Mitochondrial DNA Heteroplasmy from Childhood to Adolescence

项目摘要 慢性呼吸道疾病是一个主要的公共卫生问题， 医疗保健成本以及全球个人和家庭的严重发病率和死亡率。最近 健康和疾病的发展起源（DOHaD）领域已经证明了围产期的关键作用， 生命通过设定从胎儿/婴儿期延续的生长轨迹，在决定成人健康方面发挥作用 阶段我们认为，子宫内和婴儿期的环境金属暴露会引发不良反应， 呼吸系统健康状况在生命后期表现出来，可以在青春期首次测量， 肺的快速生长和发育。关于金属接触影响的证据，特别是混合物 在儿童时期，金属对肺部生长的影响是缺乏的，这可能解释了以后生活中的很大一部分 呼吸系统疾病的流行。这使得围产期金属暴露成为全球健康问题。的 生命早期接触金属的影响不仅因剂量而异，而且因接触时间而异。 因此，迫切需要进行研究，以更好地理解解释后者的发展窗口。 围产期暴露对生命健康的影响，以及它们影响的分子机制 孩子的肺发育 为了解决这些问题，我们将以时间和成本效益的方式对金属和 肺功能，利用肥胖，生长，环境， 和社会压力（PROGRESS）研究，这是一项在墨西哥城进行的具有良好特征的前瞻性出生队列研究。 这项拟议的研究将对600名年龄在13-16岁之间的儿童进行表型分析，这些儿童自怀孕以来一直接受随访， 从而进行一项前瞻性的纵向研究，涵盖妊娠期、婴儿期、儿童期和 青少年，并将这些数据与金标准肺生长表型相关联， 在青春期的两个时间点进行支气管扩张剂肺功能测定。我们将使用最先进的暴露生物标志物 用于通过激光烧蚀-电感耦合等离子体质谱法测量金属 从怀孕到童年，暴露具有时间敏感性，但会累积。最后，我们使用生物标记物 通过鼻细胞线粒体DNA损伤评估的累积氧化应激， 呼吸道和天然靶组织。我们的目标是使用特定剂量和时间的毒性措施 金属，以评估它们单独和作为混合物对肺生长轨迹的影响。我们假设 金属通过氧化应激对肺生长轨迹产生不利影响， 道使用鼻细胞异质性，线粒体DNA突变计数与累积 氧化应激我们预计，我们的研究结果将产生新的信息的影响，在子宫内， 早期生命金属暴露对肺功能的影响，并将为预防和治疗策略提供信息，以改善肺功能。 功能轨迹将产生终身影响。

PROJECT SUMMARY Chronic respiratory disease is a major public health problem accounting for billions of dollars in healthcare costs and substantial morbidity and mortality for individuals and families worldwide. Recently the field of Developmental Origins of Health and Disease (DOHaD) has demonstrated the key role that perinatal life plays in determining adult health by setting growth trajectories that carry forward from fetal fetal/infancy life stages. We propose that environmental metal exposures in utero and in infancy set in motion adverse respiratory health conditions that manifest later in life, and can first be measured during adolescence, a period of rapid lung growth and development. Evidence regarding the impact of metal exposure, particularly mixtures of metals, on lung growth in childhood is lacking and may explain a substantial proportion of later life respiratory disease given their prevalence. This makes perinatal metal exposures a global health concern. The effects of early life metal exposures vary based not only on dose, but also on the timing of exposure. Therefore, research is urgently needed to better understand the developmental windows that explain the later life health effects from perinatal exposures, as well as the molecular mechanisms through which they influence children’s lung growth. To address these issues we will time- and cost-effectively conduct a longitudinal study of metals and lung function by leveraging the infrastructure of the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) study, a well-characterized prospective birth cohort based in Mexico City. The proposed study will phenotype 600 children aged 13-16 years who have been followed since pregnancy, thereby conducting a prospective, longitudinal study that covers pregnancy, infancy, childhood and adolescence and linking these data with gold standard lung growth phenotyping using pre- and post- bronchodilator spirometry at two time points during adolescence. We will use state of art exposure biomarkers for metals assessed by laser ablation-inductively coupled plasma mass spectrometry to measure metal exposure in a time sensitive, yet cumulative manner from pregnancy to childhood. Finally, we use biomarkers of cumulative oxidative stress assessed by mitochondrial DNA damage in nasal cells, the upper most end of the respiratory tract, and a natural target tissue. Our goal is to use dose and time-specific measures of toxic metals to assess their effects on lung growth trajectories individually and as a mixture. We hypothesize that metals adversely affect lung growth trajectories via oxidative stress that can be estimated in the respiratory tract using nasal cell heteroplasmy, a count of mitochondrial DNA mutations correlating with cumulative oxidative stress. We anticipate that our findings will generate novel information on the impact of in utero and early-life metal exposure on lung function and will inform prevention and treatment strategies to improve lung function trajectories that will have life long impacts.