Project Summary (2005-2010)

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. The researchers’ 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, the researchers are taking the following approaches:

1.   Determining the dose response of arsenic-induced altered gene expression in fetal and neonatal lung. Their 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.   Correlating altered expression with phenotype. Protein expression patterns of genes identified as changing in a dose dependent manner in whole lung are being mapped using immunohistochemical techniques. Organ structural alterations are being determined using quantitative morphological techniques.

3.   Assessing 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 previously been regulated by DMA methylation status. Therefore, the researchers are determining 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.