Prenatal Bisphenol A and Lung Maturation

描述（由申请人提供）：超过90%的美国尿液样本检测含有可检测水平的双酚A（BPA），表明广泛和持续的接触。BPA暴露会影响特定的生命阶段，早期或新生儿暴露于低剂量BPA，导致实验动物前列腺、乳房、睾丸、乳腺的组织变化。胎儿暴露于双酚A对肺发育的影响，特别是对哮喘发病机制至关重要的气道的影响，还没有研究。诸如哮喘的气道疾病在儿童早期发展，并且在世纪后半叶经历了令人困惑的患病率增加。有一些证据表明BPA暴露与哮喘之间存在联系，小鼠母体暴露于BPA会增加后代的哮喘特征。本申请的目的是确定胎儿BPA暴露如何改变肺的传导气道中的分泌产物成熟。中心假设是BPA暴露改变了传导气道中的粘液细胞和Clara细胞的分布和丰度，以及它们的主要分泌产物。我们的初步数据支持中心假设，显示更丰富的气道上皮粘液物质在进行气道和MUC5B和CCSP的基因表达增加在胎恒河猴肺暴露于BPA。我们将通过两个特定的目标来解决中心假设，即使用特定部位的肺形态测量和BPA诱导的气道高反应性的小鼠模型来确定：1）胎儿BPA暴露对气道上皮分泌细胞成熟的影响，以及2）分泌细胞及其蛋白产物的分布和丰度是否在出生后持续改变。研究目标的完成将促进我们对两个物种（小鼠和恒河猴）产前正常分泌细胞和分泌产物成熟的理解。了解BPA对气道的影响将有助于了解BPA如何加剧以异常气道分泌物为特征的呼吸系统疾病，以及随后如何导致气道高反应性。拟议的研究使用两种动物模型来研究BPA的影响。这些研究不能在儿童中进行。这将促进我们对BPA暴露与气道疾病的潜在关系的理解，气道疾病的特征是粘蛋白分泌升高，如哮喘，这是儿童最常见的慢性疾病。 公共卫生相关性：BPA暴露会影响特定的生命阶段，早期或新生儿暴露于低剂量BPA，导致实验室动物前列腺、乳腺、睾丸和乳腺的组织变化。我们的新的初步数据表明，胎儿BPA暴露改变气道上皮细胞在肺的成熟。了解BPA对气道上皮分泌细胞的影响将有助于了解BPA如何加剧呼吸系统疾病，如儿童哮喘，其特征是气道分泌物异常。

DESCRIPTION (provided by applicant): More than 90% of all US urine samples tested contain detectable levels of bisphenol A (BPA) indicating widespread and continuous exposure. BPA exposure affects specific life stages with early pre or neonatal exposure to low dose of BPA resulting in organizational changes in the prostate, breast, testis, mammary glands of laboratory animals. The effect of fetal BPA exposures on lung development, particularly of airways which are critical for asthma pathogenesis, has not been studied. Airway diseases such as asthma develop in early childhood and have undergone a perplexing increase in prevalence in the latter half of the 20th century. There is some evidence for a link between BPA exposures and asthma, maternal exposure to BPA in mice increases hallmarks of asthma in offspring. The goal of this application is to define how fetal BPA exposure changes secretory product maturation in the conducting airways of the lung. The central hypothesis is that BPA exposure alters mucous cell and Clara cell distribution and abundance in the conducting airways, a well as their principle secretory products. The central hypothesis is supported by our preliminary data which shows more abundant airway epithelial mucosubstances in the conducting airways and increases in gene expression of MUC5B and CCSP in the fetal rhesus monkey lung exposed to BPA. We will address the central hypothesis with two specific aims that will use site-specific lung morphometry and a mouse model of BPA-induced airways hyperresponsiveness to define: 1) the effect of fetal BPA exposure on airway epithelial secretory cell maturation and 2) whether altered distribution and abundance of secretory cells and their protein products persists in the postnatal period. Completion of the research aims will advance our understanding of normal secretory cell and secretory product maturation in the prenatal period in two species, mice and rhesus macaques. Understanding of the effect of BPA on the airway will aid in understanding of how BPA may exacerbate respiratory diseases characterized by abnormal airway secretions and how this subsequently can contribute to airways hyperresponsiveness. The proposed studies use two animal models to investigate BPA effects. These studies could not be conducted in children. This will advance our understanding of the potential relationship of BPA exposure to airway diseases characterized by elevated mucin secretions, such as asthma, the most common chronic condition of childhood. PUBLIC HEALTH RELEVANCE: BPA exposure affects specific life stages with early pre or neonatal exposure to low dose of BPA resulting in organizational changes in the prostate, breast, testis, and mammary glands of laboratory animals. Our novel preliminary data show that fetal BPA exposure alters airway epithelial cell maturation in the lung. Understanding of the effect of BPA on airway epithelial secretory cells will aid in the understanding of how BPA may exacerbate respiratory diseases, such as childhood asthma, that are characterized by abnormal airway secretions.