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

Persistent Link:
http://hdl.handle.net/10150/306345
Title:
Role of In-Utero and Chronic Arsenite Exposure in the Development of Adult Cardiovascular Pathogenesis
Author:
Sanchez Soria, Pablo
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
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.
Type:
text; Electronic Dissertation
Keywords:
Cardiovascular; Chronic; Fetal; Pharmacology and Toxicology; Arsenic
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Camenisch, Todd D.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleRole of In-Utero and Chronic Arsenite Exposure in the Development of Adult Cardiovascular Pathogenesisen_US
dc.creatorSanchez Soria, Pabloen_US
dc.contributor.authorSanchez Soria, Pabloen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractArsenic 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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCardiovascularen_US
dc.subjectChronicen_US
dc.subjectFetalen_US
dc.subjectPharmacology and Toxicologyen_US
dc.subjectArsenicen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorCamenisch, Todd D.en_US
dc.contributor.committeememberCamenisch, Todd D.en_US
dc.contributor.committeememberKlewer, Scott E.en_US
dc.contributor.committeememberKlimecki, Walter T.en_US
dc.contributor.committeememberVaillancourt, Richard R.en_US
dc.contributor.committeememberGandolfi, Jayen_US
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