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质，但饮用水中摄入砷对健康的非癌症影响也会导致重大疾病，包括心血管疾病、动脉硬化、糖尿病和慢性肺部疾病。宫内或出生后早期暴露对发育变化的影响，从而导致非癌症健康影响，尚未得到研究。这项建议探讨了砷对肺部发育的影响。肺是一个发育较晚的器官，人类的生长持续到五岁以后。我们的假设是，摄入饮用水中的砷会导致子宫和出生后对肺发育至关重要的基因表达发生变化。更改中 这些基因在关键发育期的表达将导致成人的慢性疾病。为了回答这些问题，我们提出了以下目标：1)测定砷引起胎儿和新生儿肺组织基因表达改变的剂量效应。我们的初步结果表明，在这些关键时期对正常发育至关重要的细胞外基质基因会因宫内和成人暴露于砷而发生变化。2.)改变的表达与表型相关。将使用免疫组织化学技术绘制整个肺中被识别为以剂量依赖方式变化的基因的蛋白质表达模式。器官结构的改变将使用定量形态技术来确定。3.)评估叶酸缺乏和补充对砷暴露引起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DNA甲基化的改变有关。细胞外基质基因(胶原和弹性蛋白)的表达已被证明受DMA甲基化状态的调节。因此，我们将确定砷引起的胶原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。在高危人群中，膳食补充叶酸是一种潜在的干预/预防砷引起的肺部疾病的策略。

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.