Masters Theses

Date of Award

5-2005

Degree Type

Thesis

Degree Name

Master of Science

Major

Comparative and Experimental Medicine

Major Professor

Patricia K. Tithof

Committee Members

Gary S. Sayler, David Rotstein, Roger Carroll, Robert Donnell, John Sanseverino

Abstract

Exposure to environmental pollution can be a contributing factor to the development of cardiovascular disease (CVD). Due to contamination produced by long-term discharge of coal tar wastes into the creek, a 2.5-mile section of the Chattanooga Creek in south Chattanooga was designated as a Superfund site by the USEPA in 1994. In order to further investigate the potential health risks posed by creek contamination, 12 PAHs found in high levels in the sediment of the creek as compared to an uncontaminated control site were evaluated for their effects on the human coronary artery endothelial cell (HCAEC) phospholipase A2 (PLA2)/arachidonic acid (AA) cascade, a pathway known to play a significant role in endothelial cell inflammation, apoptosis, and atherosclerosis. Aortic tissue from feral mice trapped at the Superfund site exhibited an increase in markers of inflammation and apoptosis when compared to mouse tissue from the control site, suggesting that natural exposure to contaminants in the creek results in similar findings as in the in vitro studies. Six of the compounds studied (acenaphthylene, benz [e] acephenanthrylene, benzo [k] fluoranthene, fluoranthene, naphthalene, and phenanthrene) activated the AA cascade by targeting the isoform of PLA2, Group IVC PLA2. Upregulation of the enzyme was associated with an increase in apoptosis of HCAECs, as measured by 3H-AA release and histone fragmentation, as well as Western blot analysis for PARP cleavage. Transfection with siRNA specific for Group IVC decreased the amount of histone fragmentation induced by the six compounds. Two compounds (anthracene and benz [a] anthracene) were inactive. Four compounds (benzo [g,h,i] perylene, chrysene, indeno [1,2,3-c,d] pyrene, and pyrene) fluoresced independently of reagents used to measure histone fragmentation and were not able to be evaluated accurately in respect to this. However, these four compounds induced PARP cleavage and three of the four (chrysene, indeno [1,2,3-c,d] pyrene, and pyrene) produced significant 3H-AA release from HCAECs. These data suggest that PAHs present in Chattanooga Creek have potential toxic effects on the cardiovascular system both in vivo and in vitro, and confirm the need for further studies.

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