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published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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Thesis (Ph. D.)--University of Hong Kong, 2005.

M.Sc. (Biochemistry) / Manganese (Mn) is an essential trace element. Although it is vital for the normal development of mammals, too much Mn can be harmful. Most reported cases of toxicity have been found in occupational settings, such as welding, mining and ferro-manganese (FeMn) production plants. Long-term overexposure to Mn can result in lung epithelial necrosis and the development of a neurological disease, manganism. Even though evidence of Mn-associated diseases exists, some epidemiological studies have found no association between occupational exposure levels and possible indicators of neurotoxic effects. It is, therefore, important to establish Mn toxicity and the mechanisms involved in this toxicity, for a possible identification of biomarkers of exposure and effect. The hypothesis formulated states that, FeMn particulate matter consists of nano and micro sized particles that, upon inhalation, may cause injury to the lungs and translocate to the brain. Since Mn-induced injury to the brain and lungs is a possibility, this study aimed to investigate the effects of FeMn dust, which was collected from a FeMn smelter works, on primary rat astrocytes and human bronchial epithelial (BEAS-2B) cells. This was achieved by first characterizing the physicochemical properties of the particles by using a scanning mobility particle sizer (SMPS) and aerodynamic particle sizer (APS) for size distribution, Brunauer-Emmett-Teller (BET) for surface area determination and inductively coupled plasma atomic emission spectroscopy (ICP-AES) for elemental composition analysis. Cells were treated with 5, 10, 25 μg/cm2 FeMn, and particle uptake, by astrocytes and BEAS-2B cells, was confirmed using dark field microscopy e.g. Cytoviva® hyperspectral imaging system. The viability and toxicity of FeMn was studied using the conventional toxicity assay systems, including 3-bis [2-Methoxy-4- nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide salt (XTT), adenosine triphosphate (ATP) and lactate dehydrogenase (LDH) assays. It was, however, established that FeMn particles interfere with the final read-out produced by some of these assay systems. Therefore, a rare application of the xCELLigence real time cell analysis (RTCA) system was implemented, as a better option, in the assessment of the toxicity and viability of cells in the presence of FeMn particles. The ability of FeMn particles to cause deoxyribonucleic acid (DNA) damage in both cell types was also determined using the alkaline comet assay. Finally, the nuclear translocation of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and inflammatory transcription factor nuclear factor kappa B (Nf-κB), was studied using Western blotting. The results showed that FeMn, in a dose dependent manner, could enter the cell, decrease the viability, induce DNA damage, and initiate nuclear transport of the studied transcription factors. The same methodologies were implemented to determine the physicochemical properties of Min- U-Sil 5 crystalline silica, used as a positive control, to assess its toxicity and effect on cellular viability. As well as its ability to induce DNA damage and initiate nuclear translocation of the two transcription factors, in astrocytes and BEAS-2B cells. Similar to FeMn particles, crystalline silica also enters the cells with subsequent reduction in cellular viability. It results in increased DNA damage and increased nuclear translocation of the studied transcription factors. The effects of crystalline silica on these cellular effects were, however, always higher than those produced by FeMn particles. To conclude, these results indicate that depending on the size distribution of particles in the work environment, they may enter different regions of the lungs. However, for those particles in the nano size region, direct access to the brain is a possibility. These results also indicate that after deposition in the target organ, these particles will produce cellular changes through oxidative stress. This would lead to inflammation, decreased cellular viability and increased toxicity.