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Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress
Mickey, Kristen Elizabeth
Mickey, Kristen Elizabeth
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Abstract
Environmental exposure to arsenic is a worldwide health concern which is linked to a number of diseases. Areas with arsenic levels above the current safe concentration have higher levels of skin, lung, liver, and bladder cancers and non-carcinogenic pathologies, including neuropathy, cardiovascular diseases and diabetes mellitus. Understanding the mechanism by which arsenic exerts its toxic effects is crucial to developing preventative strategies and more effective treatments for individuals with long term exposure to arsenic compounds. This thesis outlines the epidemiological evidence for arsenic-linked diseases as well as the current understanding of arsenic metabolism and the mechanism(s) of how arsenic exerts its cytotoxicity. The liver is a major site of arsenic uptake and biotransformation and thus is affected by high arsenic levels. Generation of reactive oxygen species (ROS) has been shown to play a major role in the toxic effects of arsenic. Using primary and immortalized hepatocyte cell lines these studies investigate how arsenic generates the production of ROS. The localization of superoxide was shown to overlap with mitochondria and antioxidant enzymes were shown to be induced after arsenic treatment. Measurement of mitochondria function through oxygen consumption rate (OCR) shows that arsenic affects oxidative phosphorylation and the ability for mitochondria to efficiently couple electron transport with ATP production. Understanding the source of ROS from arsenic exposure and how cells cope with altered mitochondrial bioenergetics is an important building block for future studies on arsenic toxicity and for developing treatments for arsenic exposure.
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Date
2015-05-31
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University of Kansas
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Keywords
Toxicology, Cellular biology, Molecular biology, Arsenic, Mitochondria, Oxidative Stress