Maternal diabetes has adverse effects not only on oocyte quality but also on embryo development. However, it is still unknown whether the DNA imprinting in oocytes is altered by diabetes. By using streptozotocin (STZ)-induced and nonobese diabetic (NOD) mouse models we investigated the effect of maternal diabetes on DNA methylation of imprinted genes in oocytes. Mice which were judged as being diabetic 4 days after STZ injection were used for experiments. In superovulated oocytes of diabetic mice, the methylation pattern of Peg3 differential methylation regions (DMR) was affected in a time-dependent manner, and evident demethylation was observed on Day 35 after STZ injection. The expression level of DNA methyltransferases (DNMTs) was also decreased in a time-dependent manner in diabetic oocytes. However, the methylation patterns of H19 and Snrpn DMRs were not significantly altered by maternal diabetes, although there were some changes in Snrpn. In NOD mice, the methylation pattern of Peg3 was similar to that of STZ-induced mice. Embryo development was adversely affected by maternal diabetes; however, no evident imprinting abnormality was observed in oocytes from female offspring derived from a diabetic mother. These results indicate that maternal diabetes has adverse effects on DNA methylation of maternally imprinted gene Peg3 in oocytes of a diabetic female in a time-dependent manner, but methylation in offspring's oocytes is normal.
Previous studies suggest that fetuses of poorly controlled diabetic mothers display a higher incidence of malformations, primarily neural tube defects and skeletal/cardiovascular abnormalities and fetal death than those of nondiabetic pregnant mothers [1234–5]. Furthermore, their offspring are susceptible to obesity, glucose intolerance, and type 2 diabetes [6, 7]. These adverse effects may be the result of lower oocyte quality and a disturbed uterine environment. Diabetic mice have been shown to exhibit uterine atrophy [8, 9], reduced mating ability , and alterations of the hypothalamic-pituitary-ovarian axis . The ovarian function is impaired, and also the ovulation rate is lower in type 1 diabetic mice than in nondiabetic mice [9, 12].
Numerous studies have shown that if oocytes are exposed to diabetic conditions during folliculogenesis and meiotic maturation, meiotic maturation and subsequent developmental potential are negatively affected [12, 13]. Evidence suggests that the mitochondrial function, glucose metabolism pathways, and communications between cumulus cells and the oocyte are all changed in follicles of maternal diabetic mice [141516–17].
The maternal diabetic state is also detrimental to pre- and postimplantation embryo development in rodents and in humans. Preimplantation embryo development is significantly delayed in both chemically induced and spontaneous diabetic models, and the embryo has a high incidence of degeneration and fragmentation [1819–20]. Even one-cell embryos isolated from diabetic mice and transferred to nondiabetic mice still experience malformations and growth retardation in the process of development .
In order to know the mechanisms underlying these abnormal phenomena, genetic factors are of interest. Several studies have shown that gene expression in embryos is affected by maternal diabetes. [22232425–26]. However, we do not know whether the methylation status of imprinted genes in oocytes is influenced by maternal diabetes.
Epigenetics presents a link between gene and environment, and it has an important role in embryo development and diseases . A series of experiments showed that diploidy alone is not sufficient for normal embryo development, but proper regulation of both parental genomes is required as well [28, 29]. Maternal