Project 3: Pulmonary Response to Toxicants In Susceptible Population

生长发育需要基因和基因产物的时空协同表达。在这一关键时期，在子宫和出生后早期接触毒物可能会影响基因表达，改变器官结构和生理功能。然而，在这些发展的关键时期，对与环境有关的毒物暴露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存在。无论是在子宫内还是在儿童早期发育期间，饮用高水平的砷都会增加成年人死于肺癌和慢性肺部疾病的风险。我们自己在动物模型中的工作表明，在宫内和出生后早期暴露于砷之后，对乙酰甲胆碱的呼吸道反应以剂量依赖的方式增加。这种变化似乎是永久性的，对早期发育暴露的反应是特异的。虽然摄入砷的暴露会导致改变，但吸入暴露的途径也与肺部有关。在宫内和/或出生后暴露于香烟烟雾中，环境中的城市空气颗粒物或金属会导致呼吸道反应性增加，肺表面积与体积比降低，并改变后代的肺功能。因此，我们 假设在发育敏感时期吸入含砷粉尘会导致成年人的肺功能和结构改变。对吸入砷的直接影响以及吸入砷和摄入砷的潜在相互作用的评估将是本项目的重点。我们将评估四个目标。前三个目标将确定造成子代肺结构和功能改变所需的敏感暴露时间：目标1将检查吸入含砷颗粒对怀孕小鼠的影响(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。

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.