Project 3: Pulmonary Response to Toxicants In Susceptible Population

项目3：易感人群对有毒物质的肺部反应

• 批准号: 7936596
• 负责人: Robert Clark Lantz
• 金额: $ 17.59万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936596
• 关键词: Adult; Affect; Age; Air; Air Pollutants; Animal Model; Animals; Arsenic; Attention; Birth; Bladder; Breathing; Chronic; Chronic lung disease; Consumption; Data; Development; Dose; Dust; Evaluation; Exposure to; Female; Gene Expression; Growth and Development function; Health; Incidence; Inflammation; Ingestion; Kidney; Lead; Life; Liver; Lung; Malignant neoplasm of lung; Metals; Mining; Mothers; Mus; Neonatal; Organ; Particulate; Perinatal Exposure; Physiological; Population; Proteins; Reporting; Respiratory physiology; Risk; Route; Skin; Source; Structure; Surface; Time; Toxic Environmental Substances; United States; Water; Work; cigarette smoking; critical period; drinking water; early childhood; exposed human population; in utero; lung development; methacholine; offspring; particle; postnatal; pregnant; pulmonary function; pup; response; toxicant

Growth and development requires the temporal and spatial coordinated expression of genes and gene products. During this critical time, in utero and early postnatal exposure to toxicants has the potential to affect gene expression, altering organ structure and physiological function. However, only limited attention has been paid to the effects of environmentally relevant exposures to toxicants during these critical periods of development. Inorganic arsenic is a ubiquitous environmental toxicant, found in high concentrations throughout the world. Drinking water exposures to high levels of arsenic either in utero or during early childhood development led to an increased risk of dying from lung cancers and chronic lung disease in adults. Our own work in animal models has demonstrated that following in utero and early postnatal exposure to arsenic, airway response to methacholine was increased in a dose dependent manner. This change appears to be permanent and the response is specific for the early developmental exposure. While exposures from ingestion of arsenic can lead to alterations, the inhalation route of exposure is also relevant to the lung. In utero and/or postnatal exposure to cigarette smoke, ambient urban air particles or metals leads to increased airway reactivity, decreased surface to volume ratios in the lung and altered lung function in the offspring. Therefore, we hypothesize that inhalation of dusts containing arsenic during sensitive developmental times will result in altered pulmonary function and structure in adults. The evaluation of the direct effects of inhaled arsenic and the potential interactions of inhaled arsenic and ingested arsenic will be the emphasis of this project. We will evaluate four aims. The first three Aims will define sensitive exposure times necessary to produce alterations in lung structure and function in the offspring: Aim 1 will examine the effects of inhalation of arsenic and arsenic containing particles to pregnant mice (in utero exposure); Aim 2 will examine the effects of early postnatal exposures to these compounds and Aim 3 will examine the effect of combined in utero and postnatal exposures. Aim 4 will evaluate the effect of inhalation in combination with ingestion of arsenic.

生长和发育需要基因和基因产物的时空协调表达。在这一关键时期，在子宫内和出生后早期暴露于有毒物质有可能影响基因表达，改变器官结构和生理功能。然而，在这些发展的关键时期，对与环境有关的接触有毒物质的影响只给予了有限的关注。无机砷是一种普遍存在的环境毒物，在世界各地都有高浓度的发现。无论是在子宫内还是在儿童早期发育期间，饮用水中暴露于高含量的砷都会导致成年人死于肺癌和慢性肺病的风险增加。我们在动物模型中的研究表明，在子宫内和出生后早期暴露于砷后，气道对乙酰甲胆碱的反应以剂量依赖性方式增加。这种变化似乎是永久性的，反应是特定的早期发育暴露。虽然摄入砷的暴露可能导致改变，但吸入暴露途径也与肺有关。在子宫内和/或出生后暴露于香烟烟雾，周围的城市空气颗粒或金属导致气道反应性增加，肺的表面积与体积比降低，并改变后代的肺功能。所以我们 假设在敏感的发育时期吸入含砷粉尘将导致成人肺功能和结构的改变。本研究的重点将是探讨吸入砷的直接效应以及吸入砷与摄入砷的潜在交互作用。我们将评估四个目标。前三个目标将确定引起后代肺结构和功能改变所需的敏感暴露时间：目标1将检查吸入砷和含砷颗粒对怀孕小鼠的影响（子宫内暴露）;目标2将检查出生后早期暴露于这些化合物的影响，目标3将检查子宫内和出生后联合暴露的影响。目的4将评估吸入联合摄入砷的效果。