Modulation of Diabetes‐Induced Palate Defects by Maternal Immune Stimulation

Abstract

Maternal diabetes can induce a number of developmental abnormalities in both laboratory animals and humans, including deformities of the face and palate. The incidence of birth defects in newborns of women with diabetes is approximately 3 to 5 times higher than among nondiabetics. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by various etiologies including hyperglycemia. This study was conducted to determine whether nonspecific maternal immune stimulation could reduce diabetes-induced palate defects and orofacial clefts. Female ICR mice were immune stimulated before induction of hyperglycemia with Freund's complete adjuvant (FCA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFNgamma). Streptozocin was used to induce hyperglycemia (26-35 mmol blood glucose) in females before breeding. Fetuses from 12 to 18 litters per treatment group were collected on Day 17 of gestation. Palate width and length were measured, and the incidence of orofacial clefts was determined. Palate length and width were both decreased by maternal hyperglycemia. Maternal immune stimulation with GM-CSF or FCA limited the degree of palate shortening from the hyperglycemia. Each of the three immune stimulants attenuated significant narrowing of the palate. Rates of orofacial clefts were not significantly different between treatment groups. Palatogenesis is a complex process driven by cellular signals, which regulate cell growth and apoptosis. Dysregulation of cellular signals by maternal hyperglycemia can result in fetal malformations. Maternal immune stimulation may prevent dysregulation of these signaling pathways thus reducing fetal malformations and normalizing palate growth.