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

围产期金属暴露对儿童期至青春期肺功能轨迹和线粒体 DNA 异质性的影响

• 批准号: 10624291
• 负责人: Maria Jose Rosa
• 金额: $ 58.96万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-18 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624291
• 关键词: 16 year old; Ablation; Accounting; Address; Adolescence; Adult; Affect; Animals; Archives; Area; Arsenic; Biological Markers; Birth; Bronchodilator Agents; Cadmium; Cells; Child; Childhood; Cities; DNA Damage; Data; Development; Developmental Process; Disease; Dose; Early identification; Elderly; Environment; Epithelial Cells; Epithelium; Exposure to; Family; Goals; Growth; Growth and Development function; Health; Health Benefit; Health Care Costs; Impairment; Individual; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Infrastructure; Intervention; Lasers; Lead; Life; Life Cycle Stages; Link; Longitudinal Studies; Lung; Lung diseases; Manganese; Measures; Mediating; Mediation; Mediator; Metal exposure; Metals; Mexico; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morbidity - disease rate; Motion; Nasal Epithelium; Nose; Obesity; Oxidative Stress; Pattern; Perinatal; Perinatal Exposure; Persons; Phenotype; Play; Predisposition; Pregnancy; Prevalence; Prevention strategy; Prospective Studies; Prospective cohort; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Reactive Oxygen Species; Research; Respiratory Disease; Respiratory System; Risk; Risk Factors; Risk Reduction; Role; Source; Spirometry; Structure; Time; Tissues; Tooth structure; Vital capacity; age related; aged; airway epithelium; burden of illness; chronic respiratory disease; cohort; cost; cost effective; deciduous tooth; disorder risk; early life exposure; fetal; functional decline; global health; heteroplasmy; improved; in utero; infancy; innovation; lead exposure; longitudinal, prospective study; lung development; lung health; mitochondrial DNA mutation; mortality; novel; oxidative damage; perinatal environment; prenatal; prenatal exposure; prevent; prospective; pulmonary function; respiratory health; response; social stressor; temporal measurement; time interval; toxic metal; treatment strategy

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.

项目概要 慢性呼吸道疾病是一个重大的公共卫生问题，每年造成数十亿美元的损失 最近，全球个人和家庭的医疗费用以及大量的发病率和死亡率。 健康与疾病的发育起源（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/婴儿期开始的生长轨迹来决定成人的健康 我们认为，子宫内和婴儿期的环境金属暴露会产生不利影响。 呼吸道健康状况会在以后的生活中表现出来，可以首先在青春期（这个时期）进行测量 有关金属暴露（尤其是混合物）影响的证据。 金属对儿童时期肺部生长的影响是缺乏的，并且可以解释很大一部分的晚年生活 鉴于其普遍存在的呼吸道疾病，这使得围产期金属暴露成为全球健康问题。 生命早期接触金属的影响不仅取决于剂量，还取决于接触的时间。 因此，迫切需要研究来更好地理解解释后来的发展窗口。 围产期暴露对生命健康的影响，以及它们影响的分子机制 儿童肺部生长。 为了解决这些问题，我们将以时间和成本有效的方式对金属和金属进行纵向研究 通过利用肥胖、生长、环境等方面的规划研究基础设施来实现肺功能， 和社会压力源（PROGRESS）研究，一项位于墨西哥城的特征明确的前瞻性出生队列研究。 拟议的研究将对 600 名 13-16 岁儿童进行表型分析，这些儿童自怀孕以来一直受到跟踪， 进行一项涵盖怀孕、婴儿期、儿童期的前瞻性纵向研究 青春期并将这些数据与使用前后的黄金标准肺生长表型联系起来 我们将在青春期的两个时间点进行支气管扩张肺量测定。 用于通过激光烧蚀-电感耦合等离子体质谱法评估金属以测量金属 从怀孕到童年，以时间敏感但累积的方式暴露。最后，我们使用生物标志物。 通过鼻细胞线粒体DNA损伤评估的累积氧化应激，最上端 我们的目标是使用特定剂量和时间的毒性措施。 我们捕获了这些金属，以单独和混合评估它们对肺部生长轨迹的影响。 金属通过氧化应激对肺生长轨迹产生不利影响，氧化应激可以在呼吸系统中进行估计 使用鼻细胞异质性，与累积相关的线粒体 DNA 突变计数 我们预计我们的研究结果将产生关于子宫内和氧化应激影响的新信息。 生命早期金属暴露对肺功能的影响，并将为改善肺功能的预防和治疗策略提供信息 将对一生产生影响的功能轨迹。