Project 3: Pulmonary Response to Toxicants In Susceptible Population

生长发育需要基因和基因产物在时间和空间上的协调表达。在这一关键时期，在子宫内和产后早期接触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注意。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。在子宫内或儿童早期发育期间接触高浓度砷的饮用水会导致成年人死于肺癌和慢性肺病的风险增加。我们自己在动物模型中的工作表明，在子宫内和出生后早期暴露于砷后，气道对甲胆碱的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定的。虽然摄入砷可导致改变，但吸入途径也与肺部有关。在子宫和（或）出生后暴露于香烟烟雾、城市环境空气颗粒或金属会导致气道反应性增加，肺部表面积与体积比降低，并改变后代的肺功能。因此,我们

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.