Using Exhaled Breath to Evaluate the Long-term Mechanisms of Early-life Arsenic Exposure

利用呼出气评估生命早期砷暴露的长期机制

• 批准号: 9320957
• 负责人: EDWARD S SCHELEGLE
• 金额: $ 18.39万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320957
• 关键词: Adult; Age; Air Pollutants; Area; Arsenic; Biological Markers; Blood; Bronchiectasis; Chemical Exposure; Chemicals; Child; Childhood; Chile; Chronic; Cities; Data; Development; Diet; Disease; Elderly; Environmental Epidemiology; Epidemiologist; Epidemiology; Exhalation; Exposure to; Food; Functional disorder; Future; Gelatinase B; Gender; Genetic; Goals; Habits; Health; Home environment; Human; Inflammation; Interleukin-12; Interleukin-6; Investigation; Isoprostanes; Laboratory Scientists; Lead; Learning; Life; Liquid substance; Longitudinal Studies; Lung; Lung diseases; Malignant - descriptor; Malignant neoplasm of lung; Measures; Mediator of activation protein; Metabolism; Methods; Mind; Municipalities; National Research Council; Natural experiment; Non-Malignant; Oxidative Stress; Pacific Ocean; Pathology; Persons; Physiology; Planet Earth; Play; Population; Prevalence; Prevention; Process; Publishing; Pulmonary Inflammation; Pulmonary Pathology; Records; Registries; Regulation; Research; Research Infrastructure; Research Subject Recruitments; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Rivers; Role; Saliva; Sampling; Site; Smoker; Smoking; Source; Spirometry; Sputum; Tissue Inhibitor of Metalloproteinase-1; Tissues; Toxic effect; Toxicant exposure; Update; Urine; Variant; Water; Work; Workplace; biobank; cohort; comparison group; cost effective; drinking water; early life exposure; environmental agent; fetal; high risk; in utero; inflammatory marker; metabolomics; novel; screening

Millions of people in the US are exposed to arsenic in food and drinking water. Ingested arsenic is an established cause of malignant and non-malignant lung disease, with the developing lung seeming to be particularly susceptible. We have been investigating a unique situation in Chile involving >100,000 adults who were exposed to a well-documented period of high arsenic drinking water concentrations while in utero or as young children, but not later. This scenario, with its large population and excellent data on past exposure, is unprecedented in environmental epidemiology and has offered us a rare opportunity to investigate the long-term impacts of early- life exposure. To date, we have found 5-fold increases in lung cancer; 46-fold increases in bronchiectasis; 3-6 fold increases in respiratory symptoms; and lung function declines similar to those in heavy smokers. This is the first evidence ever that early-life exposure to a common environmental agent can cause such major increases in lung disease in adults. Currently, the exact pathophysiology of these effects and mechanisms by which an in utero chemical exposure can led to lung disease 40-50 years after the exposure occurred, are unknown. Exhaled breath condensate (EBC) contains hundreds of compounds thought to represent the underlying physiology or pathology of the lung, including several hypothesized to be key mediators of arsenic toxicity. Since EBC can be collected non-invasively it may offer a practical method for studying the mechanisms of arsenic-related lung disease. We propose the first investigation ever on whether EBC may be a useful medium for studying the long- term impacts of an early-life toxic exposure. Inflammation, oxidative stress, and tissue remodeling have all been hypothesized to play a role in arsenic toxicity, and biomarkers of these processes will be measured in the EBC of 75 subjects from our Chile cohort and 75 age, gender, and smoking matched unexposed controls. Subjects will be people from our ongoing study in Chile who were randomly selected from the Chile voter registry which contains 94% of all adults in Chile. Detailed data on smoking, diet, workplaces, illnesses, air pollutants, spirometry, and blood, urine, and saliva samples will also be collected. US EPA and FDA are currently evaluating the need for new regulation for arsenic in water and food. A National Research Council review of this process concluded that new mechanistic data are needed to identify susceptible sub-populations needing stricter regulatory protection and to evaluate the likelihood that toxic mechanisms and disease could occur at common US exposure levels. The advantages of this proposal are the unique cohort and its highly accurate data on past exposure; the availability of a good comparison group with little variation in major confounders; and the leveraging of our already established infrastructure and already recruited research subjects. Other advantages are that EBC contains a number of biomarkers thought to be directly relevant to arsenic toxicity, and the potential for EBC to provide a valuable non-invasive medium for directly evaluating pathology and disease mechanisms in the human lung, a primary site of arsenic toxicity.

在美国，数百万人暴露于食物和饮用水中的砷。摄入砷是一种公认的 恶性和非恶性肺部疾病的原因，与发展中的肺似乎是特别 易受影响我们一直在调查智利的一个独特情况，涉及> 10万成年人， 到一个有充分记录的高砷饮用水浓度时期，而在子宫内或幼儿， 但不是以后这种情况，由于其庞大的人口和良好的数据，过去的接触，是前所未有的， 环境流行病学，并为我们提供了一个难得的机会，调查长期影响的早期- 生活曝光到目前为止，我们发现肺癌增加了5倍，支气管扩张增加了46倍， 呼吸道症状增加一倍;肺功能下降与重度吸烟者相似。这是 这是有史以来第一次有证据表明，早期生活中暴露于一种常见的环境因素会导致如此大的增长。 在成人的肺部疾病中。目前，这些影响的确切病理生理学和机制， 子宫内化学品暴露可导致肺部疾病40-50年后发生的暴露，是未知的。呼出 呼吸冷凝液（EBC）含有数百种被认为代表潜在生理或 肺的病理学，包括几个假设是砷毒性的关键介质。由于EBC可以 非侵入性收集的，它可能为研究砷相关肺的机制提供一种实用的方法， 疾病我们提出了有史以来第一次调查是否EBC可能是一个有用的媒介，研究长期- 早期接触有毒物质的长期影响。炎症、氧化应激和组织重塑都是 假设在砷毒性中发挥作用，这些过程的生物标志物将在EBC中测量。 来自我们智利队列的75名受试者和75名年龄、性别和吸烟匹配的未暴露对照。科目 将是我们正在智利进行的研究中的人，他们是从智利选民登记册中随机挑选出来的， 占智利成年人口的94%关于吸烟、饮食、工作场所、疾病、空气污染物的详细数据， 还将收集肺量测定法、血液、尿液和唾液样本。美国环保局和FDA目前正在评估 需要对水和食物中的砷进行新的监管。国家研究理事会对这一过程的审查 结论是，需要新的机制数据来确定需要更严格的 监管保护，并评估毒性机制和疾病可能共同发生的可能性 美国暴露水平。这一建议的优点是独特的队列及其对过去的高度准确的数据 暴露;一个良好的比较组的可用性，主要混杂因素的变化很小;以及 利用我们已经建立的基础设施和已经招募的研究对象。其它优点 EBC含有许多被认为与砷毒性直接相关的生物标志物， EBC为直接评估病理和疾病机制提供了有价值的非侵入性介质 在人体肺部，砷中毒的主要部位。