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Final Progress Reports: Dartmouth College: Arsenic and Innate Immunity in Human Lung

Superfund Research Program

Arsenic and Innate Immunity in Human Lung

Project Leader: Bruce A. Stanton
Grant Number: P42ES007373
Funding Period: 2005-2021

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Final Progress Reports

Year:   2020  2013  2007 

Aims: The goal of this project is to understand how doses of arsenic that are relevant to exposures in the US impact essential cellular processes, and thereby contribute to disease. To date most studies on arsenic have examined very high levels of arsenic that are not relevant to the US population. Thus, Dr. Stanton's, Dr. Gerber's and their research team's studies are significant and novel because they examine the effects of relevant levels of arsenic on human health.

Studies and results: In studies on killifish, an environment model organism used extensively in toxicology and environmental research, the researchers have completely sequenced and annotated the transcriptome and genome, adding killifish to the list of organisms that have had their entire genome sequenced, and they have submitted a publication to the Proc. Natl Acad Sci. In this study examining the effects of arsenic on the ability of these fish to acclimate and adapt to changes in the environment (changes in the salinity of seawater), performed in collaboration with Celia Chen's project, the Bioaccumulation and Trophic Transfer of Mercury in Aquatic Food Webs and Joe Shaw at Indiana University (previously on the aquatic food webs project), the researcher's report that natural selection has led to the very tight regulation of a subset of genes, in a geographically isolated population of fish, that conveys on all members of the population the ability to acclimate to dramatic changes in salinity.

They also added two new specific aims to the project, including:

Test the hypothesis that arsenite, MMA and DMA have differential, dose dependent effects on the secretion of proinflammatory cytokines by HBE cells and human macrophages in response to Pa. Studies will be conducted to examine cytokine secretion in response to environmentally relevant levels of arsenite, MMA and DMA (0-10 ppb). These concentrations correspond to those measured in blood of humans exposed to As in drinking water and rice-base products in the US. In preliminary studies, we found that arsenite, MMA and DMA had differential, adverse effects on cytokine secretion by HBE cells (e.g., IL-6, IL-8, Gro-a, and Gro-b) and by macrophages (IL-8, IL-6 and TNF-α). Accordingly, studies are proposed to examine the dose-dependent effects of arsenite, MMA, and DMA on cytokine secretion by HBE cells and macrophages exposed to Pa.

Test the hypothesis that arsenite, MMA and DMA have differential, dose dependent effects on the expression of proinflammatory cytokines by HBE cells and macrophages in response to Pa by regulating miRNA expression. To test this hypothesis, the research team will examine the effect of arsenite, MMA and DMA on miRNA, mRNA and protein expression. Using a bioinformatic approach they will identify the arsenic regulated miRNAs that are responsible for the observed changes in cytokine secretion. Using miRNA inhibitors and mimics, and advanced molecular, biochemical and bioinformatic tools, they will also identify miRNAs that are responsible for the changes in the inflammatory response to Pa.

To investigate these new aims the team began to examine the effects of P. aeruginosa on macrophages and human airway epithelial cells and published several studies setting the background for studies to examine the effects of arsenic on the immune function of the lung (Publications 1-5, below). Moreover, in preliminary studies the team found that environmentally relevant levels of MMA and DMA (as low as 2 ppb) decrease the innate immune response of human macrophages and of bronchial epithelial cells to Pseudomonas aeruginosa, a bacterial pathogen that causes disease and death in millions of individuals in the US every year.

Significance: The researcher's studies are significant because they demonstrate that very low levels of MMA and DMA, relevant to the US population, cause significant changes in gene expression, facilitates natural selection, and adversely affect the ability of the lungs to eliminate bacterial infections. In addition, their studies identify for the first time a novel mechanism whereby arsenic causes and/or exacerbates bacterial infections in the lung, and indicate that low levels are arsenic are a risk factor for lung infections. Finally, their studies on arsenic, MMA and DMA provide essential information to stakeholders and policy makers, especially those at the FDA, as they discuss setting acceptable levels of arsenic, MMA and DMA in food consumed by the US population.

Plans: In 2014 the team of researchers will complete studies on killifish proposed in the application funded from 2008-2014, and will continue studies presented as preliminary data in the renewal application examining the low dose effects of arsenite, MMA and DMA on the innate immune response of the human lung.

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