Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


Pharmacology and Toxicology

Committee Chair

States, J. Christopher

Author's Keywords

Arsenic; Prenatal exposures; Cardiovascular disease; Liver; DNA methylation; Atherosclerosis


Arsenic--Physiological effect; Cardiovascular system--Diseases; Liver--Effect of arsenic on; Arsenic--Toxicology


Chronic arsenic exposure is associated with increased cardiovascular disease (CVD). Prenatal arsenic exposure at 49 ppm arsenic accelerates atherosclerosis underlying CVD in ApoE-/- mice, but the mechanism is unknown. This dissertation examines the mechanisms by which prenatal arsenic exposure accelerates atherosclerosis. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. I hypothesized that prenatal arsenic exposure alters liver development and primes the liver for susceptibility to other environmental insults, predisposing to liver disease and accelerated atherosclerosis in ApoE-/- mice. I showed that prenatal arsenic exposure caused subtle but significant liver damage in 10 and 24 week old ApoE-/- mice, thus increasing the risk of atherosclerosis. This arsenic-induced liver injury was characterized by increased basal levels of plasma ALT and AST (circulating markers of liver damage), and IL-6 (pro-inflammatory cytokine). Determination of the effects of prenatal arsenic exposure on Hsp70 and Hsc70 expression during pre- and postnatal development (GD18, and 3, 10 and 24 weeks) showed that Hsp70 was induced at age 3 and 10 weeks, but returned to unexposed levels by 24 weeks, thus indicating a temporal state of stress. However Hsc70 expression was not altered at any of these ages. Determination of Hsp70 and Hsc70 expression in isolated liver cell types showed that Hsp70 is expressed only in the liver hepatocytes, while Hsc70 is expressed in all liver cell types. It is likely that stressed hepatocytes can release excess Hsp70 into the circulation, thus contributing to increased atherosclerosis as reported in the literature. Hsp70 induction was also associated with increased CpG site methylation at +503 to +856 bp, thus indicating epigenetic change. Lastly, I showed that prenatal and "whole-life" arsenic exposures at lower exposures (4.9 and 1 ppm arsenic) increased atherosclerotic lesion formation in aortic aches, which was associated with altered plasma triglyceride and cholesterol. However, there was no difference in lesion formation between prenatal and "whole-life" exposures. Both exposure types also increased plasma cytokine/chemokine expression, thus indicating inflammation which is proatherogenic. Thus, infants are at high risk of developing atherosclerosis even at very low exposure levels.