Toxicological Impact of Mine Tailings Dust on Developing and Adult Lung

Problem: 

Windblown dusts are a frequent occurrence in the arid Southwestern US. These dusts, especially downwind of legacy mine tailings and smelters, can contain high levels of arsenic and other contaminants. However, little data exist concerning the exposure risks for arsenic-containing dusts and the potential interactions between arsenic ingestion in water and dust exposures.

Drs. Clark Lantz and Scott Boitano are studying the effects of dusts and metal-containing dusts on the developing and adult lung. Previous studies in their laboratories showed that early life exposures to arsenic-containing dusts can lead to altered lung function and that arsenic-induced lung alterations are dependent on both the developmental timing of exposures and the form of arsenic inhaled. Importantly, arsenic exposure can affect epithelial to mesenchymal transition (EMT), a process important for lung development, wound repair, and disease.  

Lantz and Boitano will use real-world dusts in cell culture and mouse exposure models as well as high-throughput toxicity assays to determine the overall toxicological responses and specific roles for EMT in airway epithelium exposed to realistic concentrations of arsenic through inhalation and ingestion.

Significance: 

This is the first study to attempt to decipher the impact of realistic inhalation and combined inhalation/ingestion routes of exposure to arsenicals during development.  This will provide new insights into the effects of the different routes of exposures on lung structure and function.

Specific Aims: 

Specific Aim 1. Use integrative, dissection and synergistic approaches to determine mining-associated dust toxicity on airway epithelial cells. 10% complete.  We will use a high capacity toxicity assay [xCELLigence real time cell analysis (RTCA)] on immortalized airway epithelial cells (16HBE14o- to model the conducting airway) to establish concentration-dependent toxicity of particulates with/without arsenic. We will use a high capacity RTCA to assess both cyto- and cell signaling-toxicity on complex mixtures. This approach incorporates integrative, dissection and synergistic toxicity assessments to screen for concentration responses of dusts, individual metal(oid)s and synergistic mixtures that can impact airway epithelium and underlie the development of lung disease.

Specific Aim 2. Determine if exposure to mining dusts results in airway epithelial to mesenchymal transition (EMT).  15% complete.  We will determine functional epithelial barrier alterations caused by exposure to real world mining dusts and synthetic arsenic-containing dusts as an indicator of EMT using 16HBE14o-. We will measure expression of epithelial tight junctions and the appearance of epithelial and mesenchymal markers following exposure to dust with/without arsenic and correlate EMT state with epithelial barrier function. We will determine if alterations are reversible after withdrawal of arsenic, or whether blocking specific EMT pathways (e.g., TGF-b) during arsenic exposure can prevent EMT and/or restore normal epithelial function.

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