Prenatal Tobacco Smoke and Expression in Airways

描述（由申请人提供）：代谢是消除体内外来生物的关键步骤。尽管代谢在确定污染物和致癌物的效力方面具有根本的重要性，但人们对生命早期接触这些系统对成年后这些系统表达的影响知之甚少，特别是在女性中。环境烟草烟雾（ETS）是肺部接触已知人类致癌物最普遍的来源之一。多达85%的儿童血液中可检测到可替宁水平，这一事实支持了儿童广泛接触ETS的事实。然而，早期生活暴露对成年后发病的肺部疾病（如癌症）的影响受到的关注有限。我们建议研究产前和产后暴露于ETS对空气传播致癌物靶器官（肺）中代谢和解毒酶基因表达的影响。ETS的毒性在女性人群中引起了人们的兴趣，因为与男性相比，女性患肺癌的时间更早，接触香烟的时间也更少。我们建议研究女性气道中基因表达的特异性改变。我们将通过比较暴露于老化和稀释侧流烟草烟雾的雌性小鼠与过滤空气对照小鼠的基因表达谱和组织病理学，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定义在产前或产前和产后暴露于侧流香烟烟雾的小鼠中基因表达改变的发生和持久性。我们将使用一种实验方法来识别基因的变化以及传导气道特有的病理生物学，这是与烟雾暴露和成人发病疾病（如哮喘、慢性支气管炎和肺癌）相关的许多变化的部位。核心假设是，女性在成年后发病的肺部疾病，如肺癌和哮喘，与肺部代谢激活化合物的能力有关，而这受到先前接触此类化合物的历史的深刻影响，特别是在子宫内。我们将通过3个具体目标来解决中心假设，这些目标将定义：1)产前和产后ETS暴露对成人气道基因表达的影响，2)产前ETS暴露对婴儿气道基因表达的影响，以及3)婴儿基因表达的变化会持续到成年。因此，这些研究将解决由子宫内接触环境烟草烟雾引起的成人肺部疾病的胎儿基础问题。

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.