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-g (IFNg). 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.

Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans

“…Hypertensive disorders and antihypertensive medications use in early pregnancy have both been suggested to affect fetal development through teratogenic mechanisms (van Gelder et al, 2010). Other conditions, including diabetes (Spilson et al, 2001;Hrubec et al, 2009;Stott-Miller et al, 2010), seizures (Gadoth et al, 1987;Friis, 1989), and colds (Lin et al, 2014) have also been linked to oral clefts. Whether such conditions directly or indirectly affect palatogenesis by use of medications is possible (Hviid and Molgaard-Nielsen, 2011) but unclear to date.…”

“…Other possible maternal risk factors include medication use, infections and specific health conditions (Mossey et al, 2009). In particular, diabetes (Spilson et al, 2001;Hrubec et al, 2009;Stott-Miller et al, 2010), hypertension (Hurst et al, 1995), and seizures (Gadoth et al, 1987;Friis, 1989) have been implicated as potential risk factors. Although many studies of environmental factors have been based on small sample sizes, it is unlikely that one single exposure will explain most of the risk associated with clefts, but rather that diverse exposures occurring at critical times in development will be independent contributing risk factors and together result in clefting.…”

Neural tube defects, folate, and immune modulation

“…Torchinsky and colleagues () found that nonspecific immunostimulation with injected rat splenocytes 3 weeks before mating led to a fourfold reduction in the incidence of malformed fetuses in a streptozocin‐induced diabetic mouse models. Subsequent studies have demonstrated similar reductions in NTDs and associated congenital malformations using other immune activators including: granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and interferon‐γ (IFNγ) (Hrubec et al, ), which are pleiotropic cytokines known for their roles in inflammation and immune cell regulation (Young and Hardy, ; Hamilton and Anderson, ).…”

Diverse ability of maternal immune stimulation to reduce birth defects in mice exposed to teratogens: a review

“…Using streptozotocin (STZ), a diabetogenic agent, to induce craniofacial defects in mice, Hrubec et al 15,16 reported significantly reduced maxillary and mandibular shortening in fetuses from hyperglycemic dams that also received GM-CSF or interferon-gamma (IFN-g) by IP injection. Maternal diabetes also increases cardiovascular defects in humans and rodents.…”