One-Cell Zygote Transfer from Diabetic to Nondiabetic Mouse Results in Congenital Malformations and Growth Retardation in Offspring

Abstract

Fetuses of type 1 and 2 diabetic women experience higher incidences of malformations and fetal death as compared with nondiabetics, even when they achieve adequate glycemic control during the first trimester. We hypothesize that maternal diabetes adversely affects the earliest embryonic stage after fertilization and programs the fetus to experience these complications. To test this hypothesis, we transferred either one-cell mouse zygotes or blastocysts from either streptozotocin-induced diabetic or control mice into nondiabetic pseudopregnant female recipients. We then evaluated the fetuses at embryonic d 14.5 to assess fetal growth and the presence or absence of malformations. We found that fetuses from the diabetic mice transferred at the blastocyst stage but also as early as the one-cell zygote stage displayed significantly higher rates of malformations consistent with neural tube closure problems and abdominal wall and limb deformities. In addition, both these groups of fetuses were significantly growth retarded. To determine if this phenomenon was due to high glucose concentrations, two-cell embryos were cultured to a blastocyst stage in 52 mm D-glucose or L-glucose as an osmotic control, transferred into nondiabetic pseudopregnant mice, and examined at embryonic d 14.5. These embryos did not demonstrate any evidence of malformations, however, they did experience significantly higher rates of resorptions, lower implantation rates, and they were significantly smaller at embryonic d 14.5. In summary, exposure to maternal diabetes during oogenesis, fertilization, and the first 24 h was enough to program permanently the fetus to develop significant morphological changes.

The facilitative glucose transporter GLUT3: 20 years of distinction

“…The blastocysts exposed to diabetic conditions by downregulation of GLUT3 displayed increased fetal resorptions and significant growth retardation (133). Similarly, the GLUT3 Ϫ/Ϫ embryos implanted but failed to progress past embryonic day 6.5 (42) (Fig.…”

“…In addition, Moley et al demonstrated increased apoptosis and an abnormal metabolic profile (25,88). In vitro culture in high glucose concentrations induced the same decrease in GLUT3 expression and when transferred into recipient mice, these embryos displayed intrauterine growth retardation and a high incidence of fetal resorptions (133). This group concluded that decreased expression of GLUT3 in these embryos exposed to Fig.…”

The impact of obesity on egg quality

“…Mitochondrial dysfunction has also been noted in the cumulus cells of type I diabetic mice, evidenced as decreased ATP and citrate, as well as increased apoptosis [95]. Using embryo transfer experiments, it is evident that maternal hyperglycemia present only up to the one-cell stage results in growth retardation and malformations in offspring [96]. It is clear that hyperglycemia alone has severe negative consequences for the oocyte.…”

Infertile marriage in patients with diabetes mellitus

“…Исследования на лабораторных животных показали, что даже кратковременное воздействие гипергликемии у бере-менных самок приводит к задержке развития эмбрионов [36,37]. Эмбрионы, полученные от животных в состоянии острой гипергликемии, вызванной стрептозотоцином или аллоксаном, отличались от эмбрионов здоровых особей сниженной скоро-стью дробления [36].…”

“…в эксперименте на мышах показали, что де-компенсация СД у матери во время оогенеза, зачатия и первых 24 часов после зачатия достаточны для того, чтобы «запрограм-мировать» дальнейшие морфологические отклонения у плода [37]. Даже при переносе здоровым особям эмбрионов от самок с СД отмечалось ухудшение имплантации, задержка и дефекты развития эмбриона [37]. Pavlinkova с соавт.…”