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: 10446235
• 负责人: Maria Jose Rosa
• 金额: $ 62.66万
• 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/10446235
• 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; Elderly; Environment; Epithelial Cells; Exposure to; Family; Goals; Gold; 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 of activation protein; 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; base; 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; 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; 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.

项目总结 慢性呼吸道疾病是一个主要的公共卫生问题，在 医疗保健费用以及世界各地个人和家庭的大量发病率和死亡率。最近一段时间 健康与疾病发育起源领域(DOHAD)已经证明了围产期 生命通过设定胎儿/婴儿时期的成长轨迹来决定成年人的健康 各阶段。我们认为，宫内和婴儿期环境中的金属暴露会对人体产生不利影响。 在以后的生活中表现出来的呼吸系统健康状况，并且可以首先在青春期进行测量 肺的快速生长和发育。关于金属暴露的影响的证据，特别是混合物 金属对童年时期肺生长的影响是缺乏的，这可能解释了晚年生活的相当大一部分 鉴于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。这个 早期生命金属暴露的影响不仅取决于剂量，而且还取决于暴露的时间。 因此，迫切需要研究，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及其影响的分子机制 儿童的肺部生长发育。 为了解决这些问题，我们将在时间和成本效益上对金属和金属进行纵向研究 通过利用肥胖、生长、环境、 和社会应激源(进展)研究，这是一个总部设在墨西哥城的具有良好特征的预期出生队列研究。 这项拟议的研究将对600名13-16岁的儿童进行表型分析，这些儿童自怀孕以来一直被跟踪调查。 从而进行一项前瞻性的纵向研究，涵盖怀孕、婴儿、儿童和 并将这些数据与金标准肺生长表型进行关联，使用前后 青春期两个时间点的支气管扩张剂肺活量测定。我们将使用最先进的暴露生物标记物 用激光烧蚀-电感耦合等离子体质谱测量金属评估金属 从怀孕到儿童，以一种时间敏感但累积的方式暴露。最后，我们使用生物标记物 通过鼻细胞线粒体DNA损伤来评估累积氧化应激，最高端 呼吸道和一个天然的靶标组织。我们的目标是使用剂量和时间特定的毒物措施 评估其单独和混合对肺生长轨迹的影响。我们假设 金属通过可在呼吸系统中估计的氧化应激对肺生长轨迹产生不利影响 使用鼻细胞异质性的鼻道，线粒体DNA突变的计数与累积 氧化应激。我们预计，我们的发现将产生关于子宫内和子宫内感染影响的新信息 早期接触金属对肺功能的影响，并将为改善肺的预防和治疗策略提供信息 将产生终生影响的功能轨迹。