טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAlona Feldman
SubjectEffects of Hyperglycemia on Reproduction through Altering
the Gonadotrope Epigenome
DepartmentDepartment of Biology
Supervisor Professor Melamed Philippa
Full Thesis textFull thesis text - English Version


Abstract

The number of overweight hyperglycemic young has been escalating rapidly in the past few years, and is currently estimated at one-third of young Americans. Overweight individuals characteristically suffer from menstrual irregularities, premature or delayed onset of puberty and often reduced fertility. The metabolic state is translated in the brain into altered synthesis and release of the gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH, in turn, activates pituitary luteinizing hormone (LH) which activate reproductive function. The responsiveness of the cells to GnRH, and the precise expression levels of LH and FSH are essential for the ovulatory cycle, and all are critical to reproductive function. We have shown that in states of chronic hyperglycemia, entry of high levels of glucose into the gonadotropes through the insulin-independent glucose transporter Glut1, results in a reduction of Sirtuin expression and activity levels, likely due to decreased availability of their co-factor, NAD. Reduced activity of Sirtuins leads to histone hyperacetylation and consequent changes in the epigenome, leading to aberrant gene expression. Moreover, we show that hyperglycemic state leads to aberrant upregulated expression of various genes, including those encoding chromatin modifying enzymes which remove repressive marks or add activating marks. This alteration caused various chromatin modifications which were maintained after reduction of glucose back to normal levels. The hyperglycemic state was also seen to affect expression levels of the gonadotropins and their regulators. The expression levels of FSHβ were particularly significantly reduced and remained low even after reduction of glucose levels, suggesting a long term epigenetic effect. Reduction in the ability of gonadotrope cells to synthesize and release the precise levels of gonadotropins would lead to abnormal activity of the reproductive axis, which might play a role in fertility problems of overweight suffering chronic hyperglycemia. Furthermore, we show that mammary gland epithelial cells, which also highly express Glut1, appear similarly affected by prolonged high glucose treatment. Long-term hyperglycemic exposure treatment lead to histone hyperacetylation and overexpression of Tet enzymes, which are DNA dioxygenases, suggesting aberrant regulation of gene expression and possibly to pre-disposition of breast cancer in hyperglycemic individuals.