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.