Pregnancy environment, and not preconception, leads to fetal growth restriction and congenital abnormalities associated with diabetes

Abstract

Maternal diabetes can lead to pregnancy complications and impaired fetal development. the goal of this study was to use a mouse model of reciprocal embryo transfer to distinguish between the preconception and gestational effects of diabetes. To induce diabetes female mice were injected with a single high dose of streptozotocin and 3 weeks thereafter used as oocyte donors for in vitro fertilization (iVf) and as recipients for embryo transfer. following iVf embryos were cultured to the blastocyst stage in vitro or transferred to diabetic and non-diabetic recipients. Diabetic and nondiabetic females did not differ in regard to the number of oocytes obtained after ovarian stimulation, oocytes ability to become fertilized, and embryo development in vitro. However, diabetic females displayed impaired responsiveness to superovulation. Reciprocal embryo transfer resulted in similar incidence of live fetuses and abortions, and no changes in placental size. However, fetuses carried by diabetic recipients were smaller compared to those carried by non-diabetic recipients, regardless hyperglycemia status of oocyte donors. congenital abnormalities were observed only among the fetuses carried by diabetic recipients. The findings support that the diabetic status during pregnancy, and not the preconception effect of diabetes on oogenesis, leads to fetal growth restriction and congenital deformities. The incidence of diabetes is on the rise worldwide affecting women of child-bearing age 1-3. Complications arising from the effects of maternal diabetes on fetal development include growth delay, miscarriage, stillbirth, macrosomia, and congenital malformations 4-7. Higher risk for preterm delivery was also reported 8-10. Finally, preexisting diabetes lead to increased incidence of maternal complications such as hypoglycemia, gestational hypertension, preeclampsia, preterm labor and Caesarean delivery, as well as other comorbidities 1,11-13. Early glycemic control in pregnancy is crucial for decreasing adverse outcomes. Rodent models of pregestational diabetes are usually developed by using diabetogenic agents, such as streptozotocin (STZ), to induce diabetes in females. Diabetes induced by a single high dose STZ injection has been previously shown to produce severe hyperglycemia similar to a type 1 diabetes 14. Mouse models of diabetes have already significantly contributed to the understanding of etiology and progression of diabetes 15. These models permit the control of the genetic and environmental factors that may influence the development, establishment, and complications of disease. There is an abundance of evidence indicating the presence of multiple female reproductive problems in murine models of diabetes, including delayed oocyte maturation, disruption of metabolic processes and of the epigenetic code in oocytes, reduced ovulation rates, impaired implantation, poor embryo development, and fetal malformations 16-22. These reports support the model that preconception diabetes has effects on oogenesis, female fertility, and pr...

Effect of Experimental Gestational Diabetes Mellitus on Mechanical Sensitivity, Capsaicin-Induced Pain Behaviors and Hind Paw Glabrous Skin Innervation of Male and Female Mouse Offspring

“… 52 Notably, in a STZ model of GDM in mice in which fetuses were implanted in diabetic dams through in vitro fertilization three weeks after STZ treatment, offspring displayed the same growth restriction observed in our studies, and this occurs regardless of hyperglycemia status of oocyte donors (pain and ENFD were not evaluated). 53 These data together further support the notion that the offspring phenotype observed in our studies is not due to a direct action of STZ on embryos but rather to the GDM hyperglycemia in dams. We do recognize that the GDM’s effects in offspring in rodent models are complex and other factors could play a role.…”

Germ Cell Drivers: Transmission of Preconception Stress Across Generations

“…For example, in humans, one study showed that the intrauterine environment can transmit maternal preconception stress to offspring via greater placental corticotropin-releasing factor during pregnancy ( Moog et al, 2016 ). In animal studies, transferring the embryo to a surrogate female is a powerful method that allows researchers to disentangling preconception effects on oocytes from effects in utero ( Tsai et al, 2020 ). Likewise, preconception stress in rats affects the quality of maternal behavior, another potential confounding factor ( Keller et al, 2019 ).…”

Association between neonatal hyperbilirubinemia and hypoglycemia in Chinese women with diabetes in pregnancy and influence factors

“…Hyperglycemia during pregnancy is a growing health concern for women and their infants, including pre-gestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) 1 . Diabetes in pregnancy causes short-term and long-term adverse impacts on both pregnant women (e.g., gestational hypertension, abortion, and stillbirth) and neonates (e.g., perinatal death, macrosomia, and infection).…”