Thesis (Ph. D.)--University of Texas at Austin, 2001. / "Fmet" after tRNA in title is superscript. Vita. Includes bibliographical references (leaves 102-119). Available also in a digital version from Dissertation Abstracts.

Thesis (M.S.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vi, 91 p. : ill. Includes abstract. Includes bibliographical references (p. 87-91).

published_or_final_version / Community Medicine / Master / Master of Public Health

No description available.

Intrauterine exposures to environmental factors have been hypothesized to influence the risk of breast cancer in adulthood. The majority of epidemiological studies suggest that dietary folate intake is inversely related to breast cancer, however, the evidence have been inconsistent. An animal study was performed to determine the relationship between in utero and postnatal dietary folate intervention and the risk of breast cancer in the DMBA rodent model. Supplementation of maternal and offspring diet with folic acid (5 mg/kg diet) was observed to significantly increase the risk of mammary tumor development in the offspring compared to controls (2 mg/kg diet). Maternal diet and tumor status were also found to be significant predictors of global DNA methylation. Our data suggests that high intrauterine and postnatal exposures to folic acid increases the risk of breast cancer development. Epigenetic modifications may be an underlying mechanism by which folate mediates mammary tumorigenesis in the offspring.

Intrauterine exposures to environmental factors have been hypothesized to influence the risk of breast cancer in adulthood. The majority of epidemiological studies suggest that dietary folate intake is inversely related to breast cancer, however, the evidence have been inconsistent. An animal study was performed to determine the relationship between in utero and postnatal dietary folate intervention and the risk of breast cancer in the DMBA rodent model. Supplementation of maternal and offspring diet with folic acid (5 mg/kg diet) was observed to significantly increase the risk of mammary tumor development in the offspring compared to controls (2 mg/kg diet). Maternal diet and tumor status were also found to be significant predictors of global DNA methylation. Our data suggests that high intrauterine and postnatal exposures to folic acid increases the risk of breast cancer development. Epigenetic modifications may be an underlying mechanism by which folate mediates mammary tumorigenesis in the offspring.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 92-106). Available also in a digital version from Dissertation Abstracts.

This thesis explored the use of sodium alginate-pectin-poly(ethylene oxide) electrospun fibers as a carrier to stabilize folic acid - an essential micronutrient that is susceptible to degradation when exposed to light and acidic conditions. In the first phase of this research, electrospinning behaviour of aqueous alginate-pectin solutions was investigated. Aqueous polysaccharide solutions could not be electrospun unless poly(ethylene oxide) (PEO) was added (≥20% w/w), resulting in electrospun alginate-pectin fibers that varied from fiber to fiber-bead, depending on the polymer blend ratio, and concentration of the polymer solutions. Polymer solutions properties (surface tension, viscosity, conductivity) were determined to study their effects on the electrospinning behaviour of the polymer solutions. In the second phase of this research, folic acid was incorporated into the polymer solutions and electrospun. The efficacy of these fibers in improving the stability of folic acid under different pH conditions was investigated. FTIR and NMR spectroscopies were employed to elucidate the nature of polymer-polymer and folic acid-polymer interaction. In phase three, the release behaviour of folic acid under simulated gastrointestinal conditions was evaluated. Overall, this research showed that electrospun fibers with different morphologies could be produced by manipulating the polymer concentration, polysaccharide/PEO blend ratio, extent of sonication treatment during sample preparation, and electrospinning process parameters. The positive effect of PEO on the electrospining of alginate-pectin fibers was attributed to its electrical conductivity and surface tension lowering effects on the polymer solutions. Electrospun fibers produced from the combination of alginate-pectin resulted in higher retention of folic acid compared to that of alginate alone. Folic acid encapsulated in crosslinked electrospun fibers achieved close to 100% retention when stored in the dark at pH 3 after 41 days of storage. Minimal release of folic acid from the electrospun fibers was observed at pH 3, although the release was significantly higher at pH 1.2. On the other hand, the release of folic acid was nearly 97% at pH 7.8, a condition that simulated the pH condition in the intestine. From NMR and FTIR data, the stabilization effect of electrospun fibers on folic acid was attributed to physical entrapment and not specific chemical interaction. The research suggests that ethanol-treated crosslinked alginate-pectin electrospun fibers can potentially be used as a folic acid carrier to protect the micronutrient in food products, especially acidic food products such as fruit juices and acidified beverages. / Natural Sciences and Engineering Research Council of Canada (NSERC) and Heinz Company of Canada

Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylene THF to 5-methyl THF, the carbon donor for the methylation of homocysteine to methionine. Patients with severe MTHFR deficiency (MRD) have neurologic abnormalities while a milder form (a thermolabile MTHFR variant) has been shown to be associated with coronary artery disease (CAD). Ten MRD patients, with reduced or non-detectable activity, were studied to characterize the nature of the mutation. Southern, Northern and Western analysis did not reveal any defects in the patients. These results suggest that the mutations may be minor insertions/deletions or single base substitutions that affect catalytic activity. Single strand conformation polymorphism (SSCP) analysis was used to detect base substitutions; 3 RFLPs were identified with this protocol. One was in the coding region (SphI) while the other two were in the 3$ sp prime$ untranslated region (MaeIII and MnlI). A difference in frequency of the SphI RFLP was found between control subjects and a small sample of CAD patients whose homocysteine levels were greater than the 99th percentile.

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a methyl donor for the re-methylation of homocysteine to methionine. A thermolabile variant of this enzyme, present in approximately 35% of alleles in the North American population, has been associated with cardiovascular disease, neural tube defects, and colon cancer. A cDNA of 2.2kb for human MTHFR has been expressed and results in an active enzyme, but the cDNA and genomic sequences 5' to the ATG start site have not been adequately investigated. The characterization of the 5' region of the human MTHFR gene is reported here. Four additional 5' exonic sequences were localized to a 4kb genomic fragment. The original exon 1 extends directly upstream into a 5' UTR. Three other 5' exons (two with open reading frames) are alternatively spliced into a common splice acceptor site, generating cDNAs with 4 possible 5' ends. The N-terminal peptide sequence of the porcine MTHFR has not been identified in the human sequence suggesting that the missing human coding sequence might be localized further upstream or not conserved across species. A putative chloride ion channel gene (ClC-6) was located in the opposite orientation, at 3.5kb upstream of the original ATG codon, suggesting an overlap with the MTHFR gene and potential co-localization of regulatory elements. A CpG island was identified in the region of a 5' exon (43S) suggesting that a transcription start site and a promoter might be nearby. This work is relevant in understanding the regulation of this important enzyme in folate metabolism.