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

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 an increased incidence of bronchiectasis, dyspnea, and chronic obstructive and restrictive lung disease in children and young adults exposed to arsenic in utero.
This pilot project develops and employs a human fetal lung xenograft model to determine the mechanisms of arsenic-induced disruption of human fetal lung remodeling. We perform xenotransplants of second trimester human fetal lungs, allowing study of human lung maturation and cytodifferentiation from pseudoglandular and canalicular stages of development.

Specific Aims

Develop a human fetal lung xenograft model of in utero arsenic exposure. We assess the best graft conditions, including size, site and initial stage to ensure optimal graft survival and maturation. In addition, we study the pharmacokinetic relationship between arsenic exposure in the drinking water and tissue-specific distribution of arsenic and its metabolites.

Determine the effects of environmentally relevant levels of arsenic exposure on growth kinetics, cytodifferentiation and global gene expression in the developing human lung.

Determine the epigenetic modifications induced by arsenic exposure in the human xenografts. We aim to elucidate the molecular targets and biomarkers of inorganic arsenic exposure during human lung development and to give mechanistic insight into the etiology of arsenic-induced respiratory disease and lung cancers.

Personnel

Project Leader: Monique De Paepe, MD
E-mail Address: Monique_DePaepe@brown.edu
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Research Associate: Quanfu Mao, MS
E-mail Address: Quanfu_Mao@brown.edu

Research Assistant: Sharon Chu, BS
E-mail Address: Sharon_Chu@brown.edu