Round Table “Fetal Impact of Maternal Disorders”. Presentación titulada: “Mechanisms of induction of congenital malformations in maternal diabetes”.

JAWERBAUM A

Los Cocos, Córdoba, Argentina

Simposio; III Latin American Symposium on Maternal Fetal Interaction and Placenta: Basic & Clinical Research.; 2007

Asociaciön Latinoamericana de estudio de la Interacción Materno Fetal y la placenta

Pre-gestational diabetes is associated with a 2- to 5- fold increased risk of congenital malformations. The most common malformations are neural tube and heart defects and arise before the 7th week of pregnancy. Diabetic animal models show similar malformations, and have allowed to study their mechanisms of induction. Pre-gestational diabetes is associated with a 2- to 5- fold increased risk of congenital malformations. The most common malformations are neural tube and heart defects and arise before the 7th week of pregnancy. Diabetic animal models show similar malformations, and have allowed to study their mechanisms of induction. Mainly hyperglycemia but also other changes elicited by maternal diabetes are believed to trigger a pro-inflammatory state in the embryo during early organogenesis, which is characterized by increased oxidative stress, nitrosative stress and a dysbalance in arachidonate/prostaglandin formation. Oxidative stress is  the most clearly established mechanism of induction of congenital malformations. There are increased reactive oxygen species and impaired antioxidant enzyme activities in embryos from diabetic animals, alterations related to increased apoptosis during embryo organogenesis. Nitrosative stress constitutes another mechanism involved in diabetic embryopathy. Indeed, our studies have shown elevated nitric oxide production and increased peroxynitrite formation in embryos from diabetic experimental models. In those embryos, the generation of the potent oxidant peroxynitrite impairs the morphogenic role of NO during early organogenesis and leads to direct damaging effects such as protein nitrosylation and impairment of different signaling pathways. Alterations in the metabolism of arachidonic acid impair the production of several prostaglandins (PGs) involved in developmental processes. 15deoxydelta PGJ2 is an anti-inflammatory molecule capable of reducing NO in the organogenetic embryos, but its concentrations are reduced in maternal diabetes. PGE2 has been clearly found associated with the process of closure of the neural tube, and its reduced concentrations have been closely related to the induction of neural tube defects in embryos from diabetic experimental models. On the other hand, PGI2 is capable of stimulating the production of embryonic PGE2 through a mechanism that depends on the capability of PGI2 to activate the nuclear receptor PPARdelta and to stimulate phospholipid metabolism. Both PGI2 and PPARdelta are diminished in embryos from experimental diabetic models. We investigated the effects of dietary treatments with PPARdelta activators in pregnant diabetic animals and found that these treatments were able to increase PGE2 concentrations and to reduce NO production in the developing embryos. In conclusion, overproduction of pro-inflammatory agents and defects in prostaglandin production are believed to play a major contribution to the induction of congenital malformations and to constitute putative targets for future strategies aiming to prevent diabetic embryopathy.