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Title: Regulation of one-carbon metabolism in the ovarian follicle and preimplantation embryo
Author: Pestinger, Valerie
ISNI:       0000 0004 5362 1812
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Periconceptional deficiencies in one-carbon (l-C) metabolites (e.g. folate, vitamin Bl2 and methionine) influence parental fertility and offspring health. Knowledge of l-C metabolism is limited to the liver where species-specific differences have been reported. Functionality in the ovary, germ cells and preimplantation embryo is poorly understood. The multitude of allosteric interactions involved in l-C metabolism makes it challenging to understand the principles by which this pathway is regulated. Mathematical models of this cycle, based on published enzyme kinetics and regulatory mechanisms within the liver, exist and can address this problem in part. We recently found that transcripts for specific l-C metabolism enzymes were either absent or poorly expressed in the bovine ovary and preimplantation embryo. Extending these initial observations, to include the sheep, pig, rat and human hepatocyte and granulosa cell lines, this thesis sought to increase the understanding of the regulation of l-C metabolism in the ovary and preimplantation embryo by combining experimental data with theoretical models. Experimental investigations at transcript, protein and enzyme activity levels revealed that l-C metabolism differs between the ovary and liver and also between the ovaries of different species. Variations considered primarily relate to the presence of MATII and the absence of BHMT within the ovary. Consequently, a mathematical model of hepatic methionine metabolism was modified to render it more representative for ovarian cells, particularly in the cow. Model predictions indicated that the ovary regulates methionine metabolism over a much narrower range of methionine input than the liver. Within this narrow range S-adenosylmethionine (SAM)-mediated transmethylation reactions are predicted to vary. Model predictions were tested in bovine granulosa cells cultured under various methionine concentrations (i.e. 0 to 500 J!M). Methionine adenosyltransferase 2A (MAT2A) transcript levels, de novo synthesis of SA M and the SAM:SAH (S-adenosylhomocysteine) ratio decreased with increasing methionine within the physiological range (i.e. 10 to 50 /!M). Homocysteine concentrations in spent culture media increased within the same range whereas progesterone synthesis and DNA methylation were unaffected by methionine dose. Results herein promote and support the importance of an optimal parental methionine status during the periconceptional period.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available