Biomedical Sciences ETDs

Molly Harmon

Publication Date

5-1-2016

Abstract

Numerous abandoned uranium mines (AUM) within the Navajo Nation contribute uranium (U), arsenic (As) and other metals to the soil, air and groundwater that continue to pose potential health risks to Navajo residents. The prevalence of inflammatory-related cardiovascular disease (CVD) and type 2 diabetes (T2D) has increased among the Navajo community in recent decades. Environmental exposure to metal contaminants may alter the circulation in ways that are associated with the inflammation-driven process of atherosclerotic plaque formation. Thus, we hypothesize that exposures to AUM metal contaminants are associated with pro-atherogenic changes in the circulation as evidenced by increased low-density lipoprotein (LDL) oxidation and serum inflammatory potential. To assess the relative contribution of mining metals exposures on community health, we assessed oxLDL and its relationship to CVD and T2D biomarkers in the Navajo, and then these data were linked to mining contaminant exposure metrics (water intake and urine metals). As proof-of-concept and to examine a possible mechanism, acellular assays investigated if As and U could directly oxidize purified human LDL cholesterol. Lastly, since serum represents the balance of inflammation, i.e. inflammatory potential, transcriptional responses of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and chemokine (C-C motif) ligand (CCL2) were measured from primary endothelial cells treated with participant serum. These responses were linked to mining contaminant exposures (water intake and AUM proximity). Regression modeling showed that estimated annual intake of As from drinking water is a significant predictor of oxLDL in this population, despite oxLDL levels being similar to levels in other populations without evidence of CVD. We found that As, but not U, oxidized the protein but not the lipid components of LDL cholesterol. Linear regression modeling showed that AUM proximity solely and strongly predicted serum inflammatory potential as measured by endothelial cell transcription of VCAM-1, ICAM-1 and CCL2. Taken together, our data suggest that exposure to U mining waste in a population with several CVD risk factors influences pro-atherogenic changes in the circulation, and that other exposure routes, metals, and mixtures should be investigated. Our data may aid in modifying clinical treatment decisions and exposure reduction strategies.

Keywords

Oxidized LDL, Arsenic, Uranium, Inflammation, Atherosclerosis, Inflammatory potential, Mining, Community, Low density lipoprotein

Sponsors

Minority Institutional Research Training Program (T32) National Institutes of Health Grant #5T32HL007736

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Lewis, Johnnye

Second Committee Member

Gonzales, Melissa

Third Committee Member

Hudson, Laurie

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