Date of Graduation

2016

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Family Medicine

Committee Chair

John M Hollander

Committee Co-Chair

Stephen E Alway

Committee Member

Aaron Erdely

Committee Member

Timothy R Nurkiewicz

Committee Member

I Mark Olfert

Committee Member

Emidio E Pistilli

Abstract

With every breath, we breathe in foreign materials, xenobiotic particles. These particles can interact with our tissues and influence the systems within. Airborne xenobiotic particles classically refer to ambient particulate matter (PM), but with technological advancement and the flourishing of nanotechnology, engineered nanomaterials (ENMs) have become entwined in the definition. Because the term xenobiotic particles encompasses particles with a broad range of size, shapes and chemical composition, definition of the properties that induce toxicity can be difficult, yet crucial to understand and predicting which of these characteristics is capable of inducing toxicity. This concept is crucial as nanotechnology moves forward and continues to introduce particles with new, unique properties. Beginning to identify the health impacts of xenobiotic particles it is important to consider ambient air pollution and the solid fraction of this mixture, particulate matter (PM). PM itself is a non-uniform, composite particle containing particles ranging in size and chemical composition. Further, PM composition can vary geographically and has been shown to differentially affect cardiovascular susceptibilities and outcomes. Within the Appalachian region, coal is a multi-billion dollar industry and comes in two forms: underground and surface mining. Surface mining is growing throughout the region due to its less labor-intensive methods, which employs large machinery to remove the soil and rock from on top of mineral deposits. One form of surface mining utilizes explosives to remove this overburden, mountaintop removal mining (MTM). Even though the mining companies attempt to abate fugitive dust, the populations surrounding these mining operations have a higher incidence of chronic cardiovascular disease mortality rates. This suggests that the PM created by MTM (PMMTM) may induce cardiac stress leading to cardiovascular disease. Nanotechnology is rapidly growing into a multi-billion dollar industry and is already incorporated into consumer products including everything from sporting equipment and food storage to personal care products and biomedical applications. With the rapid growth of nanotechnology, the toxicological impact of the ENMs driving expansion cannot keep pace with the advancement. Nano-sized particles differ in their physicochemical properties as compared to their micron-sized counterparts and while these properties imbue them with the novel applications driving nanotechnology, they may also be driving toxicological impacts. ENMs are carefully and methodically produced in particles of varying size, shape and chemical composition to accomplish different consumer-based end-products. Multi-walled carbon nanotubes (MWCNT) are a rapidly growing ENM with uniquely strong and electrical properties making it useful in everything from sporting equipment to electronics. Titanium dioxide (nano-TiO2) is a relatively inert ENM widely used as a photocatalyst and pigment in paints and personal care products. Exposure to these materials has shown adverse pulmonary and cardiovascular effects but the cardiac functional impacts following exposure have not been well characterized. Further, the subcellular cardiac mechanisms impacted by xenobiotic exposure have not been well defined. The mitochondrion may be a target of xenobiotic exposure propagating toxicity. Within the cardiomyocyte, mitochondrial analyses are further complicated by the presence of spatially and biochemically distinct subpopulations of mitochondria: the subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. The SSM sit below the sarcolemma while the IFM reside within the contractile apparatus. The goal of the current studies was to investigate the cardiac and mitochondrial impacts following an acute pulmonary xenobiotic exposure. To complete this goal, we utilized pulmonary exposure techniques, state of the art echocardiographic assessment, and mitochondrial functional analyses following xenobiotic exposure. Following a pulmonary exposure to PMMTM, we identified a significant decrease in cardiac ejection fraction and fractional shortening concomitant with an increase in cardiac apoptosis. Investigation into the source of apoptotic signaling suggested the mitochondria as central into apoptotic initiation and leads to both SSM and IFM respiratory dysfunction. Similarly, when we exposed animals to MWCNT we identified cardiac dysfunction developing after SSM and IFM respiratory dysfunction. Yet, further investigation into the mitochondrial affects identified that the IFM produced more reactive oxygen species (ROS) following exposure. Finally, following exposure to nano-vTiO2 cardiac diastolic dysfunction was observed indicative of restrictive filling during diastole. Following exposure, there was a significant decrease in mitochondrial respiratory function and an increase in ROS production and damage in the IFM. To attenuate the mitochondrial ROS production and damage leading to cardiac dysfunction, we utilized a novel transgenic animal overexpressing the antioxidant mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx). MPHGPx has been previously shown to be efficient in protecting the inner mitochondrial membrane (IMM) from ROS damage and preserve the mitochondrion's function and proteome. The IMM is essential to protect as the complexes within the mitochondrial electron transport chain (ETC) reside within the locale. Overexpressing mPHGPx attenuated mitochondrial ROS production and damage as well as the cardiac diastolic dysfunction observed following exposure to nano-TiO2. (Abstract shortened by UMI.).

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