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.

项目摘要 慢性呼吸道疾病是数十亿美元的主要公共卫生问题 全球个人和家庭的医疗保健成本以及大量的发病率和死亡率。最近 健康与疾病的发育起源（DOHAD）证明了围产期的关键作用 通过设定胎儿/婴儿生命延伸的生长轨迹来确定成人健康的生活。 阶段。我们提出，环境金属在子宫内的暴露和婴儿期在运动中不利 呼吸道健康状况在生命后期表现出来，可以在青少年时期进行测量 快速肺的生长和发育。有关金属暴露的影响，尤其是混合物的证据 金属，关于儿童期肺部生长的缺乏 呼吸道疾病鉴于其患病率。这使得围产期金属暴露在全球健康方面。这 早期金属暴露的影响不仅取决于剂量，而且基于暴露时间。 因此，迫切需要进行研究以更好地理解解释以后的发展窗口 生命健康对围产期暴露以及它们影响的分子机制的影响 儿童的肺部生长。 为了解决这些问题，我们将对金属和成本效益进行纵向研究 肺功能通过利用肥胖，生长，环境，环境，环境中编程研究的基础设施 和社会压力源（进度）研究，这是位于墨西哥城的特色预期出生队列。 拟议的研究将表型600名13-16岁的儿童自怀孕以来一直遵循 从而进行了一项前瞻性的纵向研究，涵盖了怀孕，婴儿期，童年和 青少年并将这些数据与黄金标准肺生长表型联系起来，并使用前后 青少年期间两个时间点的支气管扩张剂肺活量测定法。我们将使用最先进的曝光生物标志物 对于通过激光消融诱导耦合等离子体质谱法评估的金属以测量金属 从怀孕到童年的时间敏感但累积的方式暴露。最后，我们使用生物标志物 通过线粒体DNA损伤在鼻细胞中评估的累积氧化应激，最上端 呼吸道和天然靶组织。我们的目标是使用有毒的剂量和特定时间的度量 金属评估其对肺部生长轨迹的影响分别和混合物。我们假设这一点 金属通过氧化应激不利影响肺部生长轨迹，可以在呼吸中估计 使用鼻细胞异质的道，线粒体DNA突变的计数与累积相关 氧化应激。我们预计我们的发现将产生有关子宫内影响的新颖信息 早期金属在肺功能上暴露于肺功能，并将为预防和治疗策略提供信息以改善肺 功能轨迹将产生寿命很长的影响。