Prenatal Bisphenol A and Lung Maturation

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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.