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

胎儿肺发育需要肺上皮、血管和肺组织的协调重建 支持矩阵，建立有效的气体交换系统。宫内和出生后早期 暴露在环境毒物中可能会破坏这种微妙的平衡，并导致呼吸道疾病 在儿童和成人中。无机砷是一种普遍存在的环境毒物，其目标是肺部 肿瘤性和非肿瘤性终点。最近在老鼠身上的证据表明，怀孕 暴露于砷会破坏胎儿肺发育，并导致哮喘样表型 后代。对人类的研究描述了支气管扩张症、呼吸困难、慢性 宫内暴露于砷的儿童和年轻人中的阻塞性和限制性肺部疾病。这 试点项目将开发和使用人胎肺异种移植模型来确定机制 砷诱导的人胎肺重塑的破坏。我们的中心假设是：砷 暴露的人胎肺异种移植导致腺体后肺重塑中断， 通过分子和表观遗传改变来调节。我们将进行中期妊娠的异种移植 人胎肺，可以从假腺体研究人肺的成熟和细胞分化 和管状发育阶段。在特定的目标1.我们将开发人胎肺异种移植 宫内砷暴露模型。我们将评估最佳的移植条件，包括大小、地点和 最初阶段，以确保最佳的移植物存活和成熟。此外。我们会研究 饮用水中砷暴露与组织特异性的药代动力学关系 砷及其代谢物的分布。在具体目标2中，我们将确定 环境相关水平的砷暴露对生长动力学的影响。细胞分化与全球 发育中的人肺组织中的基因表达。最后，在具体目标3.我们将确定 砷暴露引起的人异种移植瘤的表观遗传修饰。这一试点项目将引领 肺内无机砷暴露分子靶点和生物标志物的阐明 发展，并可能对砷引起的呼吸道疾病和肺的病因有深入的了解 癌症。

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.