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.
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