Prenatal Bisphenol A and Lung Maturation

产前双酚 A 和肺成熟

基本信息

批准号：
8385986
负责人：
Laura S Van Winkle
金额：
$ 22.33万
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：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385986
关键词：
Abnormal airway secretion Address Adult Affect Affinity Allergic inflammation Anatomy Animal Model Animals Area Asthma Breast Cell Maturation Cells Child Childhood Childhood Asthma Chronic Clara cell Data Disease Dose Endocrine Disruptors Environment Epithelial Epithelial Cells Estrogen Receptors Exposure to Fetus Gene Expression Generations Goals Human Immune system Laboratory Animals Life Link Lung Lung diseases MUC5B gene Macaca mulatta Mammary gland Maternal Exposure Measures Membrane Modeling Monkeys Mucins Mucous body substance Mus Nuclear Hormone Receptors Organizational Change Outcome Parents Pathogenesis Perinatal Pregnant Women Prevalence Prostate Proteins Receptor Signaling Recording of previous events Research Resolution Respiratory physiology Sampling Secretory Cell Serum Site Staging Testing Testis Third Pregnancy Trimester Time Toxicant exposure Urine airway hyperresponsiveness bisphenol A cell type early childhood exposed human population fetal in vivo lung development lung maturation morphometry mouse model neonatal exposure novel offspring postnatal prenatal prenatal exposure protein expression

项目摘要

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.

描述（由申请人提供）：超过90％的美国尿液样品中，已检测到的双足A（BPA）水平，表明广泛且连续暴露。 BPA暴露会影响特定的生命阶段，而早期或新生儿暴露于低剂量的BPA，从而导致前列腺，乳房，睾丸，实验室动物的乳腺的组织变化。尚未研究胎儿BPA暴露对肺发育的影响，特别是对哮喘发病机理至关重要的气道的影响。诸如哮喘在幼儿时期发展的气道疾病，并在20世纪后半叶经历了令人困惑的患病率增加。有证据表明，BPA暴露与哮喘之间存在联系，小鼠中母亲对BPA的暴露会增加后代哮喘的标志。该应用的目的是定义胎儿BPA暴露如何改变肺部传播中的分泌产品成熟。中心假设是，BPA暴露会改变导电道中的粘液细胞和克拉拉细胞分布，并改变其主要分泌产物。我们的初步数据支持了中心假设，该数据显示了导电道中的气道上皮粘液固定，并且在暴露于BPA的胎儿恒河猴中，MUC5B和CCSP的基因表达增加。我们将以两个具体的目的来解决中心假设，这些目标将使用特定地点的肺形态计算和BPA诱导的Airway诱导的小鼠模型定义：1）胎儿BPA暴露对呼吸道上皮分泌细胞成熟的影响以及2）是否改变了分泌细胞和其蛋白质产品的分布和蛋白质产品的分布和丰富的possist persists postnatnatnatnatnatnatnatnatnatnatnatnatnatatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatnatsal persantsal persist。研究目的的完成将使我们在两个物种（小鼠和恒河猕猴）中对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理解BPA如何加剧以异常气道分泌物为特征的呼吸道疾病，以及随后如何为气道高应答性做出贡献。拟议的研究使用两种动物模型来研究BPA效应。这些研究不能在儿童中进行。这将提高我们对BPA暴露于气道疾病的潜在关系的理解，其特征是粘蛋白分泌升高，例如哮喘，这是最常见的儿童时期慢性疾病。公共卫生相关性：BPA暴露会影响特定的生活阶段，而早期或新生儿暴露于低剂量的BPA，从而导致前列腺，乳腺癌，睾丸和实验动物的乳腺的组织变化。我们的新型初步数据表明，胎儿BPA暴露会改变肺中气道上皮细胞的成熟。了解BPA对气道上皮分泌细胞的影响将有助于理解BPA如何加剧呼吸道疾病，例如儿童哮喘，其特征在于异常气道分泌。