Role of In-Utero and Chronic Arsenite Exposure in the Development of Adult Cardiovascular Pathogenesis

Abstract

Arsenic is a metalloid present throughout the world, and the primary sources of exposure are through air, soil, and water. Arsenic is currently ranked as the most hazardous substance among environmental toxicants, and is well recognized as a human carcinogen, as well as a contributor to metabolic and cardiovascular diseases. However, cardiovascular effects have been mostly evaluated in epidemiological studies, and the direct mechanisms of pathogenesis remain largely unknown. The scope of studies described in this dissertation characterizes the cardiovascular pathophysiology associated with exposure to environmentally-relevant arsenic concentrations (100 µg/L), and attempts to elucidate the molecular mechanisms behind impaired vascular function. The effects of chronic arsenic exposure on blood pressure regulation were examined using a mouse model exposed to 100 µg/L for 22 weeks. Chronic exposure to arsenic results in the development of hypertension and concentric left ventricular hypertrophy. Furthermore, data presented here demonstrates that in utero exposure contributes to the development of metabolic syndrome throughout adulthood. Results indicate the development of hyperglycemia, hypercholesterolemia and nonalcoholic fatty liver disease. Mechanistic studies demonstrate the effects of arsenicals on endothelial nitric oxide synthase (eNOS) and its role in arsenic-induced vascular relaxation impairment. Biochemical assessment of eNOS conclude that decreased nitric oxide availability does not occur through alterations in protein levels or phosphorylation changes; however, decreased activity is likely a result of protein dimer stability through alterations in zinc tetrathiolate binding.