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Title: The application of liquid chromatography-mass spectrometry to metabolomics, toxicology and systems biology
Author: Hodson, M. P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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In this thesis LC-MS has initially been applied to investigate metabolic changes associated with gender, diurnal variation and time to define how key physiological differences affect the metabolome in rats. In the case of gender, a clear metabolic separation of females from males was observed based upon the urinary excretion of a sulphated endogenous steroid metabolite and this illustrates the benefits attained by improving metabolome coverage, as this metabolite is not detected by 1H NMR spectroscopy. After development of acquisition and data processing methods, ultra performance LC-MS (and 1H NMR spectroscopy) was applied to a 3-dose level toxicological evaluation of bromobenzene. As well as increasing metabolome coverage, the sensitivity of LC-MS resulted in improved accuracy of measurement of a candidate biomarker, 5-oxoproline. This additional information lent weight to the possibility that 5-oxoproline could be used as a pre-emptive indicator of glutathione depletion (and oxidative stress) based upon smaller but convincing changes elicited in doses not found to result in the stark pathological damage of the high dose administration. LC-MS was then applied to investigations of dietary restriction, not only to characterise the metabolic changes observed due to reduce energy intake but also as a direct comparator to the bromobenzene study in an attempt to delineate the effects of reduced feeding from the toxicological impact on the metabolic profile. The metabolomic information was then combined with transcriptomic analyses to place the metabolomic output in a systems biology context. Alterations in energy metabolism were detected using both metabolomics and transcriptomics and many metabolic changes due to dietary restriction were also observed after administration of bromobenzene, particularly relating to glycolysis/gluconeogenesis, tricarboxyic acid cycle, amino acid metabolism and fatty acid metabolism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available