Prenatal Tobacco Smoke and Expression in Airways

产前烟草烟雾和气道表达

基本信息

批准号：
6889178
负责人：
Laura S Van Winkle
金额：
$ 15.08万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2007-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：代谢是消除体内异种生物的关键步骤。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，但对生命早期暴露对这些系统的成人表达的影响鲜为人知，尤其是在女性中。环境烟草烟雾（ETS）是肺部暴露于已知人类致癌物的最普遍的来源之一。多达85％的儿童的血液中可检测到的可检测水平的可检测水平的儿童，他们的血液中有多达85％的儿童的支持得到了支持。然而，早期生命暴露对癌症等成人肺部疾病的影响受到了有限的关注。我们建议研究产前和产后ETS暴露对靶器官的代谢和解毒酶的基因表达的影响，用于机载致癌物（肺）。 ETS的毒性在女性人群中引起了人们的关注，因为女性早于肺癌早，而在烟雾暴露较少之后就比男性患有肺癌。我们建议研究女性在气道中基因表达的特异性变化。我们将通过比较从暴露于暴露于良好特征的老化和稀释的侧流烟草烟雾中的雌性小鼠中获得的基因表达谱和组织病理学的基因表达谱和组织病理学来检查ETS暴露对肺部的影响。拟议的研究将使用微阵列方法来定义细胞水平，在产前或产后暴露于侧面流香烟烟雾的小鼠中的基因表达改变和持续性。我们将使用一种实验方法，该方法可以确定基因的变化以及针对导航的病理生物学的变化，这是与烟雾暴露和成人发作疾病有关的许多变化的部位，例如哮喘，慢性支气管炎和肺癌。中心假设是雌性（例如肺癌和哮喘）中的成年肺部疾病与肺部代谢化合物的能力有关，这受到事先暴露于此类化合物的史，尤其是在子宫中。我们将通过3个特定目的来解决中心假设，这些假设将定义：1）在成年气道中暴露前和产后ETS对基因表达的影响，2）产前ETS暴露于婴儿气道中基因表达的影响； 3）婴儿基因表达在成年中的变化。因此，这些研究将解决因子宫暴露于环境烟草烟雾而导致的肺成年疾病的胎儿基础。