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Grantee Research Project Results

Grantee Research Project Results

Lung, Arsenic Exposure, and Tissue Remodeling

EPA Grant Number: R834594C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834594
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Formative Center for the Evaluation of Environmental Impacts on Fetal Development
Center Director: Boekelheide, Kim
Title: Lung, Arsenic Exposure, and Tissue Remodeling
Investigators: Depaepe, Monique
Institution: Brown University , Thanos Scientific Consulting Group , Women & Infants Hospital of Rhode Island
EPA Project Officer: Louie, Nica
Project Period: December 1, 2009 through November 30, 2012
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009)
Research Category: Children's Health

Description:

Objective:

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 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 lung model to determine the mechanisms of arsenic-induced disruption of human lung remodeling. Our central hypothesis is: Arsenic exposure of human lung tissue results in disrupted postglandular lung remodeling, mediated by molecular and epigenetic alterations. We will study lung maturation and cytodifferentiation from pseudoglandular and canalicular stages of development.

Expected Results:

In Specific Aim 1, we will develop a lung 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. 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.

Supplemental Keywords:

in utero exposure, mammalian, metals, bisphenol A, developmental biology, perinatal programming; environmental management, Scientific Discipline, Health, Risk Assessment, Biology, Risk Assessments, Health Risk Assessment, bioavailability, exposure assessment, biochemical research, intrauterine exposure, developmental effects, perinatal exposure, children's health, biological pathways, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Risk Assessments, Biology, Risk Assessment, children's health, fetal exposure, biological pathways, bioavailability, developmental effects, perinatal exposure, exposure assessment


Main Center Abstract and Reports:
R834594    Formative Center for the Evaluation of Environmental Impacts on Fetal Development

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834594C001 Liver and the Metabolic Syndrome
R834594C002 Prostate and Endocrine Disruption
R834594C003 Lung, Arsenic Exposure, and Tissue Remodeling

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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