Prenatal Tobacco Smoke and Expression in Airways

描述(申请人提供)：新陈代谢是从体内清除外源物质的关键步骤。尽管新陈代谢在确定污染物和致癌物的效力方面具有基本的重要性，但人们对生命早期暴露对这些系统的成年表达的影响知之甚少，特别是在女性中。环境烟草烟雾(ETS)是肺部暴露于已知人类致癌物的最普遍来源之一。多达85%的儿童血液中可替宁检测到水平，这支持了儿童广泛接触ETS的事实。然而，早期接触对成人发病的肺部疾病(如癌症)的影响受到的关注有限。我们建议研究出生前和出生后ETS暴露对空气传播致癌物-肺的靶器官代谢和解毒酶基因表达的影响。女性人群对ETS的毒性很感兴趣，因为女性比男性更早、更少地接触香烟，从而患上肺癌。我们建议研究女性在呼吸道中基因表达的特异性变化。我们将通过比较暴露于具有良好特征的老化和稀释的侧流烟草烟雾的雌性小鼠和过滤后的空气对照小鼠的样本，来研究ETS暴露对肺部的影响。拟议的研究将使用微阵列方法在细胞水平上确定出生前或出生前和出生后暴露于侧流香烟烟雾中的小鼠基因表达改变的发生和持续时间。我们将使用一种实验方法来识别基因的变化以及特定于传导气道的病理生物学，传导气道是许多与吸烟暴露和成人发病疾病(如哮喘、慢性支气管炎和肺癌)相关的变化的部位。中心假设是，女性成人发病的肺部疾病，如肺癌和哮喘，与肺部代谢激活化合物的能力有关，这受到先前接触此类化合物的历史的深刻影响，特别是在子宫中。我们将通过三个具体的目标来解释这一中心假说：1)出生前和出生后ETS暴露对成人呼吸道基因表达的影响，2)产前ETS暴露对婴儿呼吸道基因表达的影响，以及3)婴儿基因表达的变化持续到成年。因此，这些研究将解决因在子宫内暴露于环境烟草烟雾而导致成人肺部疾病的胎儿基础。

DESCRIPTION (provided by applicant): Metabolism is a key step in eliminating xenobiotics from the body. Despite the fundamental importance of metabolism in determining the potency of contaminants and carcinogens, little is known about the influence of exposures early in life on the adult expression of these systems, particularly in females. Environmental tobacco smoke (ETS) is one of the most ubiquitous sources of pulmonary exposure to known human carcinogens. Widespread exposure of children to ETS is supported by the fact that as many as 85% of children have detectable levels of cotinine in their blood. Yet the effect of early life exposure on adult onset lung diseases such as cancer has received limited attention. We propose to investigate the effect of pre and post-natal ETS exposures on the expression of genes for metabolism and detoxification enzymes in the target organ for airborne carcinogens, the lung. ETS toxicity is of interest in the female population because women develop lung cancer earlier and after less cigarette exposure than men. We propose to investigate female specific alterations in gene expression in the airways. We will examine the effects of ETS exposures on the lung by comparing the gene expression profiles and histopathology of samples obtained from female mice exposed to well characterized aged and diluted side stream tobacco smoke with those from filtered air control mice. The proposed studies will use microarray approaches to define, at the cellular level, the occurrence and persistence of altered gene expression in mice exposed either prenatally or both pre and postnatally to side stream cigarette smoke. We will use an experimental approach that identifies changes in genes as well as pathobiology specific to conducting airways, the site of many changes associated with both smoke exposure and adult onset diseases such as asthma, chronic bronchitis and lung cancer. The central hypothesis is that adult onset lung diseases in females, such as lung cancer and asthma, are related to the ability of the lung to metabolically activate compounds and this is profoundly influenced by the history of prior exposure to such compounds, particularly in utero. We will address the central hypothesis through 3 Specific Aims that will define: 1) the effect of pre and postnatal ETS exposure on gene expression in adult airways, 2) the effect of prenatal ETS exposure on gene expression in infant airways and 3) which changes in infant gene expression persist into adulthood. These studies will thus address the fetal basis of adult diseases of the lung caused by exposure in utero to environmental tobacco smoke.