Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.

Abstract

Congenital malformations now represent the largest single cause of mortality in the infant of the diabetic mother. The mechanism by which diabetes exerts its teratogenic effects is not known. This study evaluated whether arachidonic acid might be involved, a possibility raised by the role of arachidonic acid in palatal elevation and fusion, processes analogous to neural tube folding and fusion. This hypothesis was tested in two animal models of diabetic embryopathy, the in vivo pregnant diabetic rat and the in vitro hyperglycemic mouse embryo culture. The subcutaneous injection of arachidonic acid (200-400 mg/kg per day) into pregnant diabetic rats during the period of organ differentiation (days 6-12) did not alter the maternal glucose concentration, the maternal weight gain, or the weight of the embryos. However, the incidence of neural tube fusion defects was reduced from 11% to 3.8% (P < 0.005), the frequency of deft palate was reduced from 11% to 4% (P < 0.005), and the incidence of micrognathia was reduced from 7% to 0.8% (P < 0.001). The addition of arachidonic acid to B10.A mouse embryos in culture also resulted in a reversal of hyperglycemiainduced teratogenesis. The teratogenic effect of D-glucose (8 mg/ml) in the medium resulted in normal neural tube fusion in only 32% of the embryos (P < 0.006 when compared to controls). Arachidonic acid supplementation (1 or 10 jug/ml) produced a rate of neural tube fusion (67%) that was not significantly different from that observed in controls. The evidence presented indicates that arachidonic acid supplementation exerts a significant protective effect against the teratogenic action of hyperglycemia in both in vivo (rat) and in vitro (mouse) animal models. These data therefore suggest that the mechanism mediating the teratogenic effect of an increased glucose concentration involves a functional deficiency of arachidonic acid at a critical stage of organogenesis.Although major advances have been made over the past 20 years in the prognosis of the newborn infant of the diabetic mother, no appreciable improvements have been noted in the rates of malformations seen in these infants (1, 2). Malformations have now become the leading cause of death in infants of diabetic mothers (3). Although the lesion most specific for human maternal diabetes is the caudal regression syndrome (4), spina bifida, hydrocephalus, anencephaly, and other central nervous system defects also occur at a high rate (5). This had led to studies of diabetic embryopathy focused on animal models of failure of neural tube folding and fusion. These defects can be produced by exposing either rat or mouse embryos to high concentrations of glucose in vitro, thus demonstrating that increased glucose levels alone are sufficient to produce malformations (6, 7). However, the mechanism linking hyperglycemia with malformations remains unknown. In this paper, we present evidence that exogenous arachidonic acid exerts a highly significant protective effect against the teratogenic action of hyperglycemia i...

Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro

“…The major products of lipid peroxidation, the hydroperoxides, are known stimulants of prostaglandin biosynthesis but inhibit the production of prostacyclin [54], an imbalance which may have deleterious effects on the embryo. The previous findings of a beneficial effect of arachidonic acid [33,34], prostaglandin E~ and F2c~ and prostacyclin [39] on embryos in a diabetic environment may also relate to this notion, since the supplementation of these substances may correct a possible imbalance in prostaglandin biosynthesis. Likewise, the finding of a beneficial effect of myo-inositol supplementation to high-glucose culture [39,40], compensating for a decreased embryonic uptake of this hexose [41], may be explained by a restored production of phosphatidylinositol and a subsequent normalization of phospholipase A2 activity [55].…”

“…Thus, both a high concentration of glucose [9], a low glucose concentration [31] and a high concentration of [3-hydroxybutyrate [32] have been shown to be teratogenic in vitro. Furthermore, various consequences of increased ambient glucose concentration have been suggested to play a role in the disturbed embryogenesis, such as arachidonic acid depletion [33,34], hyperaccumulation of sorbitol [35][36][37][38], deficiency of myo-inositol [36,37,[39][40][41] or alterations in trace metal concentrations of the offspring [42,43]. Mannose [44,45] and somatomedin inhibitors from serum of diabetic rats [46] also cause embryonic malformations.…”

Altered gene expression with abnormal patterning of the telencephalon in embryos of diabetic Albino Swiss mice

“…Although several teratogenic factors such as sorbitol accumulation [51], myo-inositol deficiency [19], arachidonic acid deficiency [18], altered prostaglandin metabolism [52] and increased concentration of 3-deoxyglucosone [53] are altered in embryos of diabetic pregnancy, the mechanisms by which these abnormalities lead to dysmorphogenesis have not been determined. Only recently, it has been shown that oxidative stress induced by maternal diabetes could lead to neural tube defects by impairing the expression of genes that control developmental processes [23].…”

“…abolic abnormalities including increased superoxide dismutase activity [15,16,17], reduced concentrations of myoinositol and arachidonic acid [18,19] and inhibition of the pentose phosphate shunt pathway [20]. Moreover, the frequency of embryonic malformations in diabetic pregnancy has been reported to be reduced by dietary supplements of antioxidants such as vitamin E or vitamin C [16,21,22,23] and butylated hydroxytoluene [24], suggesting that oxidative stress is involved in embryonic dysmorphogenesis.…”

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

“…Preventive strategies have been examined in laboratory animals based on knowledge of these pathways, in attempts to reduce diabetic embryopathy associated with high glucose levels. For example, birth defect incidence has been reduced in diabetic mice by dietary supplementation with myoinositol (Baker et al, 1990), arachidonic acid (Goldman et al, 1985;Pinter et al, 1986), lipoic acid (Wiznitzer et al, 1999), or antioxidants including vitamin E (Sivan et al, 1996) and vitamin C (Siman and Eriksson, 1997). Torchinsky et al (1997) stimulated uterine immune cells in pregnant mice in an attempt to reduce fetal resorptions associated with diabetes, and made the unexpected observation of significantly reduced malformed fetuses.…”