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