Prenatal Bisphenol A and Lung Maturation

描述(申请人提供)：在所有接受检测的美国尿样中，超过90%含有可检测到的双酚A(BPA)水平，表明广泛和持续接触双酚A。BPA暴露会影响特定的生命阶段，早期、早期或新生儿暴露于低剂量BPA会导致实验动物的前列腺、乳腺、睾丸和乳腺组织发生变化。胎儿双酚A暴露对肺发育的影响，特别是对哮喘发病机制至关重要的呼吸道的影响，目前还没有研究。哮喘等呼吸道疾病在儿童早期发病，并在20世纪后半叶经历了令人费解的发病率上升。有一些证据表明BPA暴露与哮喘之间存在联系，母鼠暴露于BPA会增加子代哮喘的症状。这项应用的目标是确定胎儿双酚A暴露如何改变肺传导呼吸道的分泌产物成熟。中心假说是BPA暴露改变了粘液细胞和Clara细胞在传导气道中的分布和丰度，以及它们的主要分泌产物。这一中心假说得到了我们的初步数据的支持，这些数据显示，在双酚A暴露的恒河猴胎肺中，呼吸道上皮细胞中有更丰富的粘膜基质，MUC5B和CCSP的基因表达增加。我们将以两个特定的目标来解决中心假说，这将使用特定部位的肺形态计量学和双酚A诱导的呼吸道高反应的小鼠模型来确定：1)胎儿双酚A暴露对呼吸道上皮分泌细胞成熟的影响；2)分泌细胞及其蛋白产物的分布和丰度的改变是否持续到出生后。研究目标的完成将促进我们对小鼠和恒河猴这两个物种在出生前正常分泌细胞和分泌产物成熟的理解。了解双酚A对呼吸道的影响将有助于理解双酚A如何加重以呼吸道分泌物异常为特征的呼吸系统疾病，以及这如何随后导致呼吸道高反应性。拟议的研究使用两个动物模型来研究双酚A的影响。这些研究不能在儿童身上进行。这将增进我们对双酚A暴露于以粘蛋白分泌增加为特征的呼吸道疾病的潜在关系的理解，例如哮喘，这是儿童最常见的慢性疾病。 公共卫生相关性：双酚A暴露会影响特定的生命阶段，早期、早期或新生儿暴露于低剂量双酚A会导致实验动物的前列腺、乳腺、睾丸和乳腺的组织变化。我们新的初步数据显示，胎儿暴露于双酚A可改变肺内呼吸道上皮细胞的成熟。了解双酚A对呼吸道上皮分泌细胞的影响将有助于理解双酚A如何加重呼吸道疾病，如儿童哮喘，其特征是呼吸道分泌物异常。

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.