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Abstract

The current epidemic of metabolic and cardiovascular disease is highlighted by the prevalence of type 2 diabetes mellitus (T2DM), a devastating disease that is growing at an astounding rate. Calorically-dense diets and physical inactivity, both of which have seen similarly dramatic increases in the past few decades, are only two amongst a myriad of risk factors contributing to metabolic dysfunction and T2DM. In recent years, more attention has turned toward other environmental factors that may be playing a role in exacerbating metabolic disease pathogenesis. Epidemiological studies have linked exposure to environmental pollutants known as endocrine disrupting chemicals (EDCs) with obesity, insulin resistance and T2DM. Additionally, numerous biochemical, cellular and animal models have shown that these EDCs have the capacity to alter normal hormonal signaling pathways both in vitro and in vivo. Exposure to arsenic (As), a toxic metalloid element, has been previously linked to chronic human disease states, including various cancers and metabolic diseases, in epidemiological studies. Recent studies estimate that over 100 million people worldwide are exposed to dangerously high levels of arsenic in their drinking water and through dietary sources.,As a result of these observations, the experiments described in this dissertation were conceived and executed in order to elucidate the mechanisms driving metabolic impairment resulting from arsenic exposure in vivo. In a mouse model characterizing chronic exposure to inorganic arsenic via drinking water, impairments in normal glucose metabolism are described. Collectively, the data from these experiments suggest that defective insulin secretion, as opposed to insulin resistance, drives the diabetogenic effects of arsenic exposure. Furthermore, dietary stress in the form of high-fat diet (HFD) feeding is shown to play an important role in arsenic- mediated metabolic dysfunction, and dietary manipulation proves to be a useful tool for studying the mechanisms driving environmentally mediated disease. In order to impact public policy and bring about meaningful change in the way environmental chemical exposure is handled, it is necessary to provide data for how these exposures directly impact human health. The research described in this dissertation makes significant strides in characterizing chronic arsenic exposure as it relates to metabolic disease pathogenesis.

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