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Title: The effect of maternal nutrition on the epigenetic regulation by DNA methylation of hepatic genes involved in glucose and fat metabolism in the offspring
Author: Hoile, Samuel P.
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2011
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Altered maternal nutrition during pregnancy induces persistent phenotypic changes in offspring, which can be transmitted between generations and are associated with differences in disease risk. Epigenetic processes have been shown to underlie the effects of the early life environment on phenotype. It is not known if epigenetic marks are transferred directly between generations or established de novo in each generation. The extent to which induced changes in phenotype and epigenotype are affected by different nutrients and the timing of nutritional change, and the stability of such effects during the life course are also not known. This thesis describes a series of experiments to address these issues. To investigate the mechanism by which induced phenotypic and epigenetic traits are transmitted between generations, dietary energy was increased 25% at conception in FO female rats and maintained at this level to the F3 generation. Body weight, energy intake, glucose and lipid homeostasis and the expression of specific hepatic genes in the pregnant dams differed between generations. In offspring, fasting glucose and fatty acid homeostasis was dysregulated in the F1 generation, but showed progressively improved metabolic control in subsequent generations despite continued exposure to the high energy diet. The effects on plasma glucose concentration were associated with altered mRNA expression and promoter methylation of phosphoenolpyruvate carboxykinase (PEPCK). Altered DNA methylation was associated with changes in the epigenetic regulation of DNA methyltransferase (DNMT) 3a2. Protein restriction of the maternal diet modified the trajectory of changes in maternal and offspring phenotype, gene expression and epigenome between generations. These findings suggest that the changes in signals from mother to the fetus, induced by differences in the interaction between maternal phenotype and nutrition in each generation, provided a stimulus for modification of the phenotype of the offspring. Such effects appeared to produce beneficial adjustments in metabolic control via altered epigenetic control of specific genes. The effects of different maternal nutritional exposures on the epigenetic regulation of specific genes was investigated by comparing differences in gene regulation following feeding of a protein restricted, 7 and 21 % safflower oil and fish oil diets during pregnancy. No offspring showed altered methylation of the PEPCK promoter, whereas feeding altered fat diets lead to significant changes in the promoter methylation of fads2. This suggests that alterations in the epigenetic regulation of transcription of specific genes are related to the nature of the nutritional challenge. In order to determine whether induced changes in the epigenetic regulation of genes are influenced by the timing of the nutritional challenge during the life course, folic acid supplementation was provided during pregnancy or to the offspring during their juvenile-pubertal (JP) period. Compared to prenatal folic acid supplementation, JP supplementation led to increased PEPCK and DNMT3a2 mRNA expression, and altered promoter methylation contingent on sex. This may be due to specific windows of plasticity in the epigenome. Differences in methylation of PEPCK and DNMT3a2 induced during development were found to change with increasing age. This suggests continued plasticity of the epigenome beyond the immediate developmental period. Overall, the findings of these studies show that the nature of induced phenotypes involves signals produced by the interaction of the mother and her environment, and the timing and nature of the nutritional challenge acting via the epigenome. Such induced traits may confer harm or benefit both within and between generations according to the nature of the nutritional exposure.
Supervisor: Burdge, Graham ; Lillycrop, Karen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics