Pulmonary Response to Arsenic in Susceptible Populations:

虽然砷长期以来一直被认为是一种人类致癌物，但饮用水中摄入砷对健康的非癌性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。子宫内或产后早期暴露对发育改变、导致非癌性健康影响的影响尚未得到研究。本提案探讨砷在肺中的发育影响。肺是一种发育较晚的器官，人类的肺在5岁以后还在继续生长。我们的假设是，饮用水中的砷摄入导致子宫和出生后对肺发育重要的基因表达发生改变。蚀变的

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.