Date of this Version
Grealish, Reilly. Arsenic Toxicity and Mitochondrial Metabolism in Astrocytes. Honors Thesis. University of Nebraska-Lincoln, 2018.
The various cells that support neurons in both the central and peripheral nervous systems are known collectively as neuroglia, or glia. Astrocytes, a type of glial cell found exclusively in the central nervous system (i.e. the brain and spinal cord), are particularly abundant and serve many functions. One of the most important is the role these cells play in the brain as a defense against harmful substances, many of which can be found in the environment and make their way into the human body as xenobiotic substances. Elemental arsenic in its inorganic form occurs naturally throughout the Earth’s crust, but poses a major health risk worldwide when it is found at elevated levels particularly in groundwater used as a source for domestic or agricultural use. Exposure to arsenic has been shown to cause a number of adverse health effects, from cardiovascular and liver damage to neurological dysfunction, though much less is known about its effects in the brain. Astrocytes are likely to play a protective role in the form of a barrier capable of detoxifying inorganic arsenic molecules carried to the brain via the circulatory system. However, the mechanism(s) by which the process of detoxification occurs has yet to be fully elucidated. Using primary astrocyte cultures, the present study focused on the role of glutathione, glucose metabolism, and mitochondria in minimizing the adverse neurological effects of xenobiotic arsenic in astrocytes. Results show that the introduction of arsenic compounds to cultures of astrocytes stimulates changes in intracellular glucose metabolism, altering flux of glucose-derived carbons through the glycolytic and oxidative pathways. The diversion has been indicated to result in an increased anaplerotic synthesis of glutathione, an important intracellular tripeptide for xenobiotic defense. In addition, results suggest that mitochondria rely on the input of acetyl-CoA, which, surprisingly, alludes to the importance of fatty acid metabolism as the alternate carbon source for acetyl-CoA in the mitochondrial contribution to detoxification of arsenic via glutathione synthesis.