Superfund Research Program
Toxicological Impact of Mine Tailings Dust on Developing and Adult Lung
Project Summary (2015-2017)
Dusts in the arid US Southwest, especially downwind of legacy mine tailings and smelters, such as the Iron King Mine and Humboldt Smelter Superfund site (IKMHSS), can contain high levels of arsenic and other contaminants. Inhalation of these dusts can lead to adverse health outcomes. Little data exist concerning the risk from exposure to arsenic-containing dusts and the potential interactions between arsenic ingestion in water and dust exposures. Epithelial to mesenchymal transition (EMT) is a vital process for appropriate organ development, is also important in epithelial wound repair, and plays a role in disease processes. Disruption of EMT during embryological development results in altered organ development while alterations in adults can result in dysfunctional wound healing that includes loss of epithelial barrier function and epithelial remodeling that increases risk for respiratory diseases.
The overall objective of this research project is to determine the toxicological responses and specific roles for EMT in the airway epithelium following dust and arsenic inhalation exposures that exist around legacy mining sites. The researchers are using dust and arsenic samples in in vivo model toxicity assays and in vitro primary cell culture mechanistic assays to determine if dust-borne arsenic elicits toxic effects by EMT disruption during development and in adult tissue.
In primary airway epithelial cell cultures the investigators are measuring expression of epithelial and mesenchymal markers in control and arsenic-exposed cells and correlating EMT state with epithelial barrier function and cellular signaling. They are also determining if alterations are reversible after withdrawal of arsenic, or whether blocking specific EMT pathways can prevent EMT and/or restore normal epithelial function following arsenic-induced changes. Initial studies are being conducted in mouse models to inform further aims and take advantage of abundant tissue. These results are being verified in studies using human cells to validate human toxicity measures.
In vitro mechanistic studies are being validated in in vivo mouse models. Researchers are determining the impact of arsenic/dust inhalation on EMT in during in utero and early postnatal lung development. They are comparing and contrasting the effects of in vivo exposure to arsenic and arsenic-containing dusts in adults with results from exposures during development to identify or rule out consistent molecular targets for arsenic-induced EMT during development (EMT type I) and in adults (EMT type 2).
The use of real world dusts and concentrations in this study is anticipated to generate data that will inform risk assessment to humans from similar exposures. In addition, by combining in vitro and in vivo toxicity measurements with the chemical and physical characterization of arsenicals in the dust, researchers will be able to determine dust arsenical properties that predict toxicity.