LOW-DOSE ARSENIC IMPACTS INNATE IMMUNE RESPONSE IN BRONCHIAL EPITHELIAL CELLS

arsenic is an environmental chemical of great concern because of its widespread presence in drinking water and its pleiotropic effects on human health. At high concentrations, which are endemic to Asia and South America, arsenic is a carcinogen, causes developmental, reproductive, neurological, and cardiac disease, and increases morbidity and mortality from infectious lung diseases. in the US, ~25 million people are exposed to arsenic in well water that exceeds the EPA drinking water standard of 10 ppb, and recent studies have additionally identified rice, rice based products and fruit juices as significant sources of organic arsenic exposure. Since little is known about the biological effects low-dose arsenic exposure, the goal of my research is to test the hypothesis that inorganic and organic forms of arsenic at levels relevant to the US population adversely affect the innate immune response in human bronchial epithelial (HBE) cells. in preliminary experiments, I used a bioinformatic approach to identify genes and signaling pathways that were affected by environmentally-relevant exposure to Dimethylarsinic Acid (DMA), an organic form of arsenic that is present in rice and rice-based products, and is the predominant form of arsenic detected in human blood. Analysis of global mRNA and microRNA expression in HBE cells revealed that DMA induced the expression of two microRNAs that target a signaling pathway critical for Vitamin D Metabolism and production of the antimicrobial peptide cathelicidin, an important component of the antimicrobial defense response. My postdoctoral Research Training will prepare me to identify additional novel research avenues using a variety of bioinformatic techniques, and to test these hypotheses using molecular methods in the laboratory. Thus, I will investigate the overarching research hypothesis in two specific aims. in Aim 1, I will use a bioinformatic approach to identify biological processes affected by Low-dose monomethylarsonous acid (MMA) and inorganic arsenic (iAs), and to compare biological networks disrupted by arsenic exposures. in Aim 2, I will investigate the hypothesis, derived from my preliminary bioinformatic analysis, that DMA disrupts a signaling pathway critical for Vitamin D Metabolism, and production of the antimicrobial peptide cathelicidin. Research Training through this fellowship will expand my ability to use bioinformatic approaches to discover novel pathways affected by arsenic, and will provide new data that addresses how arsenic affects innate immune pathways at levels relevant to the US. This data will provide relevant and timely information as the FDA considers Guidelines for organic and inorganic arsenic in food.