Project 3: Human Fetal Lung, Arsenic Exposure, Tissue Remodeling

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Fetal lung development requires coordinated remodeling of pulmonary epithelium, vasculature and supporting matrix to establish an effective gas exchange system. Intrauterine and early postnatal exposure to environmental toxicants may disrupt this delicate balance and result in respiratory morbidity in children and adults. Inorganic arsenic is a ubiquitous environmental toxicant that targets the lung with both neoplastic and non-neoplastic endpoints. Recent evidence in mice suggests that gestational exposure to arsenic disrupts fetal lung development and results in an asthma-like phenotype in the offspring. Studies in humans described increased incidence of bronchiectasis, dyspnea, chronic obstructive and restrictive lung disease in children and young adults exposed to arsenic in utero. This pilot project will develop and employ a human fetal lung xenograft model to determine the mechanisms of arsenic-induced disruption of human fetal lung remodeling. Our central hypothesis is: Arsenic exposure of human fetal lung xenotransplants results in disrupted postglandular lung remodeling, mediated by molecular and epigenetic alterations. We will perform xenotransplants of 2nd trimester human fetal lungs, allowing study of human lung maturation and cytodifferentiation from pseudoglandular and canalicular stages of development. In Specific Aim 1. we will develop a human fetal lung xenograft model of in utero arsenic exposure. We will assess the best graft conditions, including size, site and initial stage to ensure optimal graft survival and maturation. In addition. we will study the pharmacokinetic relationship between arsenic exposure in the drinking water and tissue-specific distribution of arsenic and its metabolites. In Specific Aim 2. we will determine the effects of environmentally relevant levels of arsenic exposure on growth kinetics. cytodifferentiation and global gene expression in the developing human lung. Finally, in Specific Aim 3. we will determine the epigenetic modifications induced by arsenic exposure in the human xenografts. This pilot project will lead to the elucidation of molecular targets and biomarkers of inorganic arsenic exposure during lung development and may give insight into the etiology of arsenic-induced respiratory disease and lung cancers.