Thesis (Ph. D.)--University of Queensland, 2003. / Includes bibliographical references.

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A. method for the synthesis of S³⁵-BAL has been described S³⁵-sulphate was reduced to the sulphide and converted to NaS³⁵H. The NaS³⁵H was then reacted with 2:3-dibromopropanol to form S³⁵-BAL. The product was characterized by sulphydryl content, preparation of two crystalline dithiolans, sulphur analysis and chromatographic behavior. The metabolism of S³⁵-BAL was studied in the Wistar rat. The isotopic BAL was administered by intraperitoneal injection and the S³⁵ content of the post-inject ion urine was studied. The maximum rate of S³⁵ excretion in the urine was observed in the first 6 hours after injection and was followed by a rapid decrease in S³⁵ excretion. This was true for both neutral S³⁵- sulphur and inorganic S³⁵-sulphate. The amount of neutral sulphur excreted in the urine also reached a maximum in the first 6 hours and returned to normal within 12 hours. The excretion of inorganic sulphate, however, remained abnormally high throughout the experiment. Approximately 4 - 19% of the excreted was S³⁵ in the form of inorganic sulphate while less than 0.5% was present in the ethereal sulphate. Six possible metabolic products were detected by radiochromatographic studies of the post-injection urine. These compounds were found to have the following Rf values when the chromatograms were run in a tertiary butanol-water solvent (70/35): Compound 1 0.07 - 0.10 Compound 2 0.25 - 0.30 Compound 3 0.45 - 0.50 Compound 4 0.60 - 0.65 Compound 5 0.78 - 0.85 Compound 6 0.95 - 0.98 Compound 1 was characterized as inorganic sulphate while compound 5 was found to be a thiol compound which arose following acid hydrolysis of compound 3. Extraction studies showed only compound 2 to be extracted with ether while all but compounds 1 were found to be soluble in n-butanol. Compound 4, the major metabolite, was shown to be only slightly soluble in n-butanol and insoluble in ether. No glucuronide of BAL or its metabolites have been found in the urine and no increase in glucuronic acid excretion was observed following BAL injection. The presence of a large amount of glucose in the post-injection urine was indicated by chromatographic studies. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

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Background: Over 200 million individuals worldwide are chronically exposed to arsenic (As) in drinking water at concentrations above the World Health Organization (WHO) guideline of 10 µg/L. Arsenic exposure is of particular concern in Bangladesh, where it is estimated that 35-77 million people are exposed to As in well water at concentrations above the WHO guideline. Chronic As exposure is associated with neurological impairments, respiratory disease, cardiovascular disease, skin lesions, and cancers of the skin, liver, lung and bladder. The mechanisms of As toxicity in humans are not well-characterized: there are considerable interspecies differences in As toxicokinetics, and until recently, there were no animal models to study As carcinogenesis. However, two of several proposed pathways of As toxicity in humans involve DNA methylation and oxidative stress. Arsenic metabolism, DNA methylation, and glutathione (GSH) are metabolically connected through the one-carbon metabolism and transsulfuration pathways, and their interactions are remarkably complex. The epidemiologic studies in this dissertation are designed to address the overarching hypothesis that one-carbon metabolism and the transsulfuration pathway interact to influence susceptibility to As toxicity. Introduction: Arsenic is methylated in the liver to monomethyl (MMA) and dimethyl (DMA) arsenical species by arsenic(III)-methyltransferase (AS3MT), which requires a methyl group from S-adenosylmethionine (SAM) and the presence of a reductant, such as glutathione (GSH). SAM is the universal methyl donor for transmethylation reactions, including DNA methylation, and is a product of folate-dependent one-carbon metabolism. GSH is the primary endogenous antioxidant and determinant of the intracellular redox state, and the rate-limiting precursor for GSH synthesis, cysteine (Cys), is a product of the transsulfuration pathway. One-carbon metabolism and the transsulfuration pathway are connected through homocysteine (Hcys). In humans, aberrant DNA methylation, oxidative stress, hyperhomocysteinemia (HHcys), and impaired As methylation capacity have been identified as risk factors for As-related conditions, including As-induced skin lesions. However, there are knowledge gaps regarding the relationships among these risk factors in humans, namely (1) the dose-response relationship between chronic As exposure and global DNA methylation over a wide range of As concentrations, as well as the influence of As exposure on the newly-discovered epigenetic modification, 5-hydroxymethylcytosine (5hmC); (2) whether an oxidized GSH redox state impairs the capacity to methylate As and DNA; and (3) whether variants in one-carbon metabolism genes are associated with HHcys and susceptibility to As-induced skin lesions. Methods: We addressed these questions in five self-contained epidemiological studies of As-exposed Bangladeshi adults, which employed cross-sectional (Chapters 3-6) and nested case-control (Chapter 7) designs. First, we examined the dose-response relationship between As exposure and global methylation of peripheral blood mononuclear cell (PBMC) DNA (Chapter 3). Second, we optimized a high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to measure global 5-methylcytosine (5mC) and 5hmC content in human DNA samples, and we examined the associations of As exposure with global %mC and %hmC in two independent samples of As-exposed adults (Chapter 4). Third, we measured GSH and its "oxidized" form, glutathione disulfide (GSSG) in plasma, and we examined the interaction of plasma GSH redox state and folate nutritional status on As methylation capacity (Chapter 5). Fourth, we examined the relationships between blood GSH redox, blood SAM, and global methylation of PBMC DNA (Chapter 6). Fifth, we conducted a nested case-control study (Chapter 7) to determine whether nonsynonymous single nucleotide polymorphisms (SNPs) in methylene-tetrahydrofolate reductase (MTHFR) and other one-carbon metabolism genes were associated with HHcys and risk for As-induced precancerous skin lesions, and we conducted an exploratory genome-wide association study (GWAS) of Hcys in a subset of participants. Results: Chronic As exposure was associated with increased global DNA methylation over a wide range of well water As concentrations (Chapter 3), but the relationship between As exposure and global %hmC was gender-specific, with a positive association in males and negative association in females (Chapter 4). We found that an oxidized GSH redox state was associated with both decreased As methylation capacity (Chapter 5) and global DNA hypomethylation (Chapter 6). Finally, in the nested-case control study, we confirmed previous findings that serum HHcys was a risk factor for As-induced skin lesions, and gene variants in MTHFR were found to explain a substantial proportion of the variance in serum Hcys concentrations (Chapter 7). However, we did not find that one-carbon metabolism gene variants were risk factors for As-induced skin lesions. The GWAS of serum Hcys identified one genome-wide significant SNP in the pregnane X receptor (PXR) gene, along with other SNPs in genes involved in cell signaling and the establishment of epithelial cell polarity. Taken together, our findings suggest that indices of one-carbon metabolism and the transsulfuration pathway--DNA methylation, GSH redox, and As methylation--interact with one another to influence susceptibility to As toxicity in humans. In addition, to our knowledge, this is the first report of an association between As exposure and global 5hmC.

Thesis (M.S.)--Rochester Institute of Technology, 2007. / Typescript. Includes bibliographical references (leaves 33-36).

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Arsenic contamination in drinking water is a severe problem worldwide. The best way to prevent hazardous diseases from chronic arsenic exposure is to remove the exposure. Efforts to remediate arsenic in drinking water have taken two tracks. One is to provide surface or shallow well water sources as an alternative to the arsenic contaminated deep wells. Another approach is to remove arsenic from the contaminated water. Different removal technologies like oxidation, chemical coagulation, precipitation, adsorption and others are available. There are problems and benefits associated with each of these approaches that can be related to cultural, socio-economic and engineering influences. The method proposed in this research is adsorption of arsenic to iron coated limestone. Different iron coated limestone samples were prepared. Standard solutions of 100ppb arsenic were prepared and batch and kinetic experiments were conducted. The final solution concentrations were analyzed by Graphite Furnace Atomic Adsorption Spectroscopy (GFAAs) and the results showed that iron coated limestone removed arsenic below 10ppb with 5 grams of material. Variations in iron coverage impacted efficiency of arsenic removal.