DIABETIC ENVIRONMENT AND GENETIC PREDISPOSITION AS CAUSES OF CONGENITAL-MALFORMATIONS IN NOD MOUSE EMBRYOS

Congenital malformations such as neural tube defects and a kinky or waved vertebral column were observed at higher incidence in embryos from nonobese diabetic (NOD) female mice with overt diabetes (NOD-D; 40.3%, P < 0.005) or without overt diabetes (NOD-N; 8.4%, P < 0.05) than in control Institute of Cancer Research (ICR) mouse embryos (1%) at day 13 of gestation. In vivo and in vitro preimplantation development of NOD-N, NOD-D, and ICR embryos did not differ in rate of development, size, or morphology. Embryos cultured from one-cell to early blastocyst stage were mutually transferred to uterine horns of pseudopregnant females between NOD-D and ICR mice and examined at day 13 of gestation. There were significant decreases in ratios of implantation and of viable embryos in ICR embryos transferred to NOD-D recipients (52%, P < 0.001 and 14%, P < 0.001, respectively) compared with those ratios in ICR embryos transferred to ICR uteri (79.2 and 56.2%) or those in NOD-D embryos transferred to ICR uteri (70.3 and 33.1%). Furthermore, 18 of 45 viable ICR embryos transferred to NOD-D dams had malformations, whereas there were no malformations in 73 viable ICR embryos transferred to ICR recipients, suggesting deleterious effects of maternal diabetic environment to embryos. On the other hand, 8 of 58 viable NOD-D embryos that were cultured in vitro and transferred to ICR uteri had malformations such as neural tube defects. This study suggests that both the presence of diabetes in the mother and a distinct genetic predisposition in embryos are involved as causes of the high incidence of congenital malformations in NOD-D embryos.