Pulmonary Response to Arsenic in Sus

Sus 中砷的肺部反应

• 批准号: 6901469
• 负责人: Robert Clark Lantz
• 金额: $ 16.4万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901469
• 关键词: DNA methylation; arsenic; carcinogens; dietary supplements; environmental exposure; environmental toxicology; extracellular matrix; folate deficiency; gene expression; immunocytochemistry; laboratory mouse; lung development; nutrition related tag; phenotype; water pollution

While arsenic has long been recognized as a human carcinogen, the non-cancerous health effects of arsenic ingestion in the drinking water can also lead to significant disease, including cardiovascular disease, arteriosclerosis, diabetes and chronic pulmonary disease. The effects of in utero or early postnatal exposure on alterations in development, leading to non-cancerous health effects have not been studied. This proposal explores the developmental effects of arsenic in the lung. The lung is a late developing organ, with growth continuing past the age of five years in humans. Our hypothesis is that ingestion of arsenic in drinking water results in altered in utero and postnatal gene expression important in lung development. Alteration in expression of these genes during critical developmental periods will result in chronic disease in the adult. To answer these questions, we propose the following Aims: 1.) Determine the dose response of arsenic-induced altered gene expression in fetal and neonatal lung. Our preliminary results indicate that extracellular matrix genes that are important for proper development during these critical periods are altered by in utero and adult exposures to arsenic. 2.) Correlate altered expression with phenotype. Protein expression patterns of genes identified as changing in a dose dependent manner in whole lung will be mapped using immunohistochemical techniques. Organ structural alterations will be determined using quantitative morphological techniques. 3.) Assess effects of folic acid deficiency and supplementation on alteration of gene expression and phenotype induced by exposure to arsenic. Altered gene expression following arsenic exposure has been correlated with altered DMA methylation. Expression of extracellular matrix genes (collagen and elastin) has been shown to be regulated by DMA methylation status. Therefore, we will determine whether arsenic-induced alteration in expression of collagens and elastin are correlated with methylation status. In humans, the nutritional state of folate was correlated with DMA methylation, and supplementation with folate is protective against several types of birth defects. Dietary folate supplementation represents a potential intervention/prevention strategy for lung disease induced by arsenic in populations at risk.

虽然砷长期以来一直被认为是人类致癌物质，但饮用水中摄入砷的非癌症健康影响也可能导致重大疾病，包括心血管疾病，动脉硬化，糖尿病和慢性肺病。尚未研究子宫内或产后早期暴露对发育变化的影响，从而导致非癌症健康影响。这项提案探讨了砷对肺发育的影响。肺是一个发育较晚的器官，在人类中，生长持续到五岁以后。我们的假设是，饮用水中的砷摄入的结果在改变子宫内和出生后的基因表达肺发育的重要。的改变 这些基因在关键发育期的表达将导致成年人的慢性疾病。为了回答这些问题，我们提出了以下目标：1。确定砷诱导的胎儿和新生儿肺基因表达改变的剂量反应。我们的初步研究结果表明，细胞外基质基因是重要的适当发展，在这些关键时期被改变，在子宫内和成人暴露于砷。2.）的情况。将改变的表达与表型相关联。将使用免疫组织化学技术绘制整个肺中被鉴定为以剂量依赖性方式变化的基因的蛋白质表达模式。将使用定量形态学技术确定器官结构变化。3.）第三章评估叶酸缺乏和补充对砷暴露诱导的基因表达和表型改变的影响。砷中毒后基因表达的改变 暴露与DMA甲基化改变相关。细胞外基质基因（胶原蛋白和弹性蛋白）的表达已被证明是由DMA甲基化状态调节。因此，我们将确定砷诱导的胶原蛋白和弹性蛋白表达的改变是否与甲基化状态相关。在人类中，叶酸的营养状态与DMA甲基化相关，补充叶酸可以预防几种类型的出生缺陷。膳食叶酸补充剂是一种潜在的干预/预防策略，在高危人群中由砷引起的肺部疾病。