Effects of Early Life Exposure to Household Air Pollution on DNA Methylation and Respiratory Disease in Guatemalan Children from the Household Air Pollution Intervention Network (HAPIN) Trial

项目总结 使用固体燃料造成的家庭空气污染(HAP)估计导致40万人患有慢性阻塞性肺病 每年都有慢性阻塞性肺病(COPD)死亡。尽管儿童时期的肺功能和下呼吸道疾病是决定因素 在晚年，很少有关于早年接触羟基磷灰石对呼吸健康影响的研究 在童年时。我们提出了一项HAP研究设计，该设计通过以下方式对新出现的慢性呼吸影响敏感 包括三个关键特征：1)评估早期生命易感窗口中的暴露，2)强有力的 由随机干预引入的暴露对比，以及3)预测慢性病的敏感终点 晚年的疾病。由于肺部发育迅速，妊娠期和婴儿期是易感性的关键窗口。 以前的HAP干预试验在减少HAP暴露方面只有低到中等的效果。这个 家庭空气污染干预网络(HAPIN)试验(2017-2021年)提供了一项具有时间敏感性的独特研究 机会，因为液化石油气(LPG)炉灶和燃料干预降低了中位妊娠 危地马拉参与者的细颗粒物(PM2.5)暴露量减少77%，从98微克/立方米增加到23微克/立方米。干预措施 一直持续到1岁，收集了广泛的健康数据，包括肺炎的发病率和严重程度。 我们一直保持对干预后队列的跟踪，评估HAP暴露和儿童2岁时的成长 年加上3岁时的肺功能。我们假设儿童肺功能和下呼吸道疾病 发作是与成年COPD有关的HAP健康影响的敏感指标。DNA甲基化(DNaM) 婴儿期的肺炎可能会影响儿童后期的这些呼吸终点。我们建议 利用我们在危地马拉成功的液化石油气烹饪干预措施来调查早期接触HAP的影响 并探索dNaM作为生物标记物的作用。我们假设随机的液化石油气 烹饪干预和较低的PM2.5和黑碳(BC)暴露将与1岁时的dNaM相关 4-7岁时肺功能较强，下呼吸道疾病较少。目标1.估计影响 在妊娠期和婴儿期(年龄和1岁)(目标1.A)和HAP期间随机进行液化石油气烹饪干预 干预(Aim1.B)期间和之后暴露(PM2.5和BC)对肺功能轨迹(3-7岁)的影响 呼吸道疾病发病率较低(4~7岁)。目的2.评估随机液化石油气的效果 妊娠期和婴幼儿早期(1岁)的烹饪干预(目标2.A)和HAP暴露(目标2.B) 在干预期(1岁)结束时对dNaM生物标志物的影响。目标3.确定dNaM是否在年龄 1岁(Aim3.A)和1岁以前的肺炎发作(Aim3.B)与肺功能有关 3至7岁儿童的运动轨迹和较低的呼吸道疾病发病率。早期生活中高密度脂蛋白对健康的影响 童年后期的肺功能和下呼吸道疾病对早期生活有重要意义。 暴露于HAP的人群中COPD的起源，并识别可能支持这一点的表观遗传学变化 这种关系可以带来更好的研究和干预。

PROJECT SUMMARY Household air pollution (HAP) from solid fuel use causes an estimated 400,000 chronic obstructive pulmonary (COPD) deaths each year. Although lung function and lower respiratory disease in childhood are determinants of COPD risk later in life, there are few studies of the influence of early life HAP exposure on respiratory health later in childhood. We propose a HAP study design that is sensitive to emerging chronic respiratory effects by incorporating three key features: 1) assessment of exposure during early life windows of susceptibility, 2) a strong exposure contrast introduced by a randomized intervention, and 3) sensitive endpoints that predict chronic disease later in life. Gestation and infancy are critical windows of susceptibility due to the rapid lung development. Previous HAP intervention trials had only low to moderate effectiveness for reducing HAP exposure. The Household Air Pollution Intervention Network (HAPIN) trial (2017-2021) offers a time-sensitive, unique research opportunity because the liquefied petroleum gas (LPG) stove and fuel intervention lowered median gestational fine particulate matter (PM2.5) exposure in Guatemalan participants by 77%, from 98 to 23 µg/m3. The intervention continued until age 1 year and extensive health data were collected, including pneumonia incidence and severity. We have maintained follow-up of the cohort post-intervention, assessing HAP exposure and child growth at age 2 years plus lung function at age 3 years. We posit that childhood lung function and lower respiratory disease episodes are sensitive indicators of HAP health effects that relate to adulthood COPD. DNA methylation (DNAm) and pneumonia during infancy may influence these respiratory endpoints later in childhood. We propose to leverage our successful LPG cooking intervention in Guatemala to investigate effects of early life HAP exposure on longer-term respiratory health and explore DNAm as a biomarker. We hypothesize that the randomized LPG cooking intervention and lower PM2.5 and black carbon (BC) exposure will be associated with DNAm at age 1 year and greater lung function and fewer lower respiratory disease episodes at age 4-7 years. Aim 1. Estimate effects of a randomized LPG cooking intervention during gestation and infancy (age <1 year) (Aim 1.A) and HAP exposure (PM2.5 and BC) during and after the intervention (Aim1.B) on lung function trajectories (age 3-7 years) and lower respiratory disease incidence (ages of 4 to 7 years). Aim 2. Estimate effects of a randomized LPG cooking intervention (Aim 2.A) and HAP exposure (Aim 2.B) during gestation and early infancy (age <1 year) on DNAm biomarkers at the end of the intervention period (age 1 year). Aim 3. Determine whether DNAm at age 1 year (Aim3.A) and pneumonia episodes until age 1 year (Aim 3.B) are associated with lung function trajectories and lower respiratory disease incidence between ages of 3 to 7 years. Effects of early life HAP on lung function and lower respiratory disease later in childhood would have important implications for the early life origins of COPD in populations exposed to HAP, and identifying epigenetic changes that might underpin this relationship could lead to improved research and interventions.