Insights on arsenic-mediated oxidative stress, mitochondrial dysfunction, and cardiovascular disease progression
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This dissertation contributes to the literature on arsenic and health, identifying four areas for specific investigation. Chapter 1 addresses arsenic in the environment examining its impact on public health in high and low exposure populations. Chapter 2 examines possibilities for ameliorating the toxicity of arsenic in real world contexts. This chapter is published in the Journal Toxics (doi:10.3390/toxics5040038). Chapter 3 investigates the association between metabolic syndrome and arsenic methylation capacity in a low exposure population, showing a positive association between methylation capacity and metabolic syndrome in a sample drawn from the U.S. National Health and Nutrition Examination Survey (NHANES) population. This chapter is under preparation for journal submission. Chapter 4 experimentally assesses the differential toxicity of trivalent inorganic arsenic (iAs(III)) and the metabolite trivalent monomethylarsonous acid (MMA(III)) in vascular smooth muscle cells, and our data show increased toxicity of MMA(III) relative to iAs(III) in VSMCs with mitochondrial dysfunction as a central component of toxicity. This chapter is published in the journal Toxicology in Vitro (https://doi.org/10.1016/j.tiv.2016.06.006). Chapter 5 provides a summary, conclusions, and recommendations for future research. Methodologically, this dissertation is composed of a review and synthesis of published data, a secondary data analysis from an epidemiology perspective, and an original study of experimental data. Each chapter addresses gaps in the current literature pertaining to various aspects of arsenic and cardiovascular disease. The dissertation as a whole contributes to our understanding of a significant and ubiquitous environmental toxin. This research is important and innovative because it applies diverse methodologies to study arsenic and cardiovascular disease. The selected methodologies are relevant in the fields of environmental science and epidemiology. This research has implications for millions of individuals exposed to arsenic through contaminated ground water around the world as well as among select arsenic-exposed populations in the U.S., and provides the foundation for future exploration of the selective toxicity of arsenic and its metabolites to mitochondria, the relevance of arsenic methylation capacity as a risk factor for the health effects of arsenic, and a framework for developing antioxidant solutions to the global problem of arsenic induced cardiovascular toxicity. In chapter 2 we reviewed 25 studies that assessed the effects of non-enzymatic antioxidants against arsenic exposed mitochondria and/or cardiovascular cells and tissues. We report that arsenic impairs all aspects of mitochondrial function and mitigates apoptosis by elevating reactive oxygen species (ROS). The antioxidants presented in this review largely prevented arsenic-induced pathology in vivo and in vitro. Compared to arsenic treatment alone, co-treatment with phytonutrient antioxidants restored cardiac function, reduced ROS levels, restored antioxidant activities, reduced apoptosis, reduced calcium overload, restored ATP content, and restored the activity of mitochondrial complexes. We suggest that future studies directly compare antioxidant compounds against arsenic-induced cardiovascular dysfunction, and we encourage the development of mitochonrially targeted antioxidant nanoformulations to improve antioxidant bioavailability. In chapter 3 we report a positive association between increased arsenic methylation and metabolic syndrome in women with normal BMI, and among obese women after controlling for statistically significant and literature justified covariates. Our data suggest that gender and BMI modify the association between arsenic methylation and metabolic syndrome. Additionally, we report that arsenic methylation patterns in our sample are similar to reports of methylation capacity in populations with significantly higher arsenic exposure. Based on these results, we suggest that future studies evaluate the effectiveness of the current maximum contaminant level (MCL) for arsenic on preclinical biomarkers for cardiovascular disease in a model that establishes causality. In chapter 4 we demonstrate increased toxicity of the arsenic metabolite MMA(III) relative to iAs(III) in VSMCs. We report for the first time that MMA(III) promotes mitochondrial dysfunction and oxidative stress in VSMCs, and that these deficits stem from the generation of mitochondrial and non-mitochondrial ROS following exposure to MMA(III). This work warrants future studies that probe for molecular mechanisms by which MMA(III) selectively targets mitochondria and elicits the release of superoxide in VSMCs. The results from chapter 4 (increased toxicity of methylated arsenic species) support our results from chapter 3, in which we demonstrate that increased arsenic methylation is associated with increased odds of metabolic syndrome, presumably due to the elevated presence of toxic methylated species that result from increased arsenic methylation. Data from chapters 3 and 4 support the premise that increased arsenic methylation increases the concentrations of toxic methylated arsenic species in the body, resulting in increased rates of ROS production, and contributing to disease status. Our results from chapter 2 (antioxidant amelioration of arsenic-induced cardiovascular dysfunction) provide recommendations for future research on the prevention of arsenic-induced cardiovascular disease.