(Project 5: Zhang, Boitano, Lantz) Chronic exposure to arsenic-containing dusts from the Iron King Mine Superfund Site, and other hardrock (metal) mining sites in arid and semi-arid climate is of public health importance worldwide. Both cancer and non-malignant lung diseases are associated with chronic arsenic exposure. While arsenic is classified as a carcinogen following either ingestion or inhalation, little data exist concerning the modes of action for development of noncancerous lung diseases from exposure to arsenic containing dusts through inhalation. Noncancerous lung diseases that have been associated with arsenic ingestion include both obstructive (chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis) and restrictive (fibrosis) lung disease. Preliminary data from Project 4 and others suggest that inhalation of arsenic associated with particulates may be an important exposure route for lung toxicity. Collectively, data indicate that arsenic exposure compromises the barrier integrity of the airway epithelium by inducing an epithelial to mesenchymal transition (EMT). This project will examine a potential intervention to block arsenic toxicity. Nrf2 is a transcription factor that is activated by oxidative stress. Activation of the canonical Nrf2 pathway leads to expression of genes that can protect against increased oxidative stress. The Zhang team's studies (and others) indicate a protective role for Nrf2 against arsenic exposure. However, the molecular mechanisms of how Nrf2 protects airway epithelial cells, specifically, how activation of Nrf2 pathways can modulate EMT and airway epithelial barrier function, is not known. The hypothesis of Project 5 is that arsenic-containing dusts cause airway epithelial dysfunction through autophagy blockage/prolonged Nrf2 activation (non-canonical); however, intermittent induction of Nrf2 (canonical) by dietary supplementation during exposure can maintain airway epithelial barrier integrity, and thus, reduce arsenic-induced lung disease. These differential outcomes are indicative of a ?dark side? of Nrf2 that may contribute to arsenic toxicity. We will examine this hypothesis in the following three Specific Aims.
In Aim 1, we will determine the protective role of Nrf2 in maintaining airway epithelial barrier integrity in response to dust particles with/without arsenic in vitro. We will then, in Aim 2, determine the molecular mechanisms of Nrf2 induction (canonical vs non-canonical) by dust particles with/without arsenic in vitro. Finally, in Aim 3, we will examine the efficacy of prophylactic canonical Nrf2 activation by dietary supplementation in maintaining airway epithelial barrier integrity and ameliorating lung damage in mice exposed to inhaled dust particles with/without arsenic. Impact: Dietary Nrf2 activation may counteract arsenic-mediated inhalation toxicity to lung epithelium, providing an intervention for populations at high risk of arsenic exposure. A detailed understanding of the mechanism of Nrf2 activation by arsenic dusts and its effects on airway epithelial cells will prove extremely valuable in the generation of preventive and therapeutic strategies for the populations at risk of exposure to arsenic, and potentially, other metal(oids).

Public Health Relevance

(Project 5: Zhang, Boitano, Lantz) Arsenic is a contaminant of soils that can be transported in dust particles and inhaled, causing respiratory and lung diseases. This project aims to investigate the detailed mechanism by which arsenic lung inflammation and malfunction occur. In turn, this will allow us to develop disease-preventive treatments for the populations at risk of arsenic dust inhalation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004940-29
Application #
9537576
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
29
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Khan, Muhammad Amjad; Ding, Xiaodong; Khan, Sardar et al. (2018) The influence of various organic amendments on the bioavailability and plant uptake of cadmium present in mine-degraded soil. Sci Total Environ 636:810-817
Yellowhair, Monica; Romanotto, Michelle R; Stearns, Diane M et al. (2018) Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells. Toxicol Appl Pharmacol 349:29-38
Fu, Xiaori; Dionysiou, Dionysios D; Brusseau, Mark L et al. (2018) Enhanced effect of EDDS and hydroxylamine on Fe(II)-catalyzed SPC system for trichloroethylene degradation. Environ Sci Pollut Res Int 25:15733-15742
Duncan, Candice M; Brusseau, Mark L (2018) An assessment of correlations between chlorinated VOC concentrations in tree tissue and groundwater for phytoscreening applications. Sci Total Environ 616-617:875-880
Virgone, K M; Ramirez-Andreotta, M; Mainhagu, J et al. (2018) Effective integrated frameworks for assessing mining sustainability. Environ Geochem Health 40:2635-2655
Namdari, Soodabeh; Karimi, Neamat; Sorooshian, Armin et al. (2018) Impacts of climate and synoptic fluctuations on dust storm activity over the Middle East. Atmos Environ (1994) 173:265-276
Hossein Mardi, Ali; Khaghani, Ali; MacDonald, Alexander B et al. (2018) The Lake Urmia environmental disaster in Iran: A look at aerosol pollution. Sci Total Environ 633:42-49
Dehghani, Mansooreh; Fazlzadeh, Mehdi; Sorooshian, Armin et al. (2018) Characteristics and health effects of BTEX in a hot spot for urban pollution. Ecotoxicol Environ Saf 155:133-143
Pu, Mengjie; Guan, Zeyu; Ma, Yongwen et al. (2018) Synthesis of iron-based metal-organic framework MIL-53 as an efficient catalyst to activate persulfate for the degradation of Orange G in aqueous solution. Appl Catal A Gen 549:82-92
Brusseau, Mark L; Guo, Zhilin (2018) The integrated contaminant elution and tracer test toolkit, ICET3, for improved characterization of mass transfer, attenuation, and mass removal. J Contam Hydrol 208:17-26

Showing the most recent 10 out of 497 publications