Mechanisms of induction of embryonic and placental alterations in maternal diabetes

JAWERBAUM A

Madrid, España

Simposio; Simposio Internacional de Bioquïmica perinatal; 2008

Fundación Areces

Mechanisms of induction of embryonic and placental alterations in maternal diabetes Alicia Jawerbaum. Laboratory of Reproduction and Metabolism. CEFYBO-CONICET. School of Medicine, University of Buenos Aires. Buenos Aires, Argentina.   Maternal diabetes is associated with an increased risk of defects in embryonic, fetal and placental development. Diabetic animal models show similar developmental defects and allow the study of their mechanisms of induction. Mainly hyperglycemia but also other changes elicited by maternal diabetes are believed to trigger a pro-inflammatory state in the intrauterine environment, which is characterized by increased oxidative stress, nitrosative stress, matrix metalloproteinases overexpression and a dysbalance in prostaglandins formation. Oxidative stress is  the most clearly established mechanism of induction of congenital malformations. There are increased reactive oxygen species (ROS) and impaired antioxidant enzyme activities in embryos, fetuses and placentas from diabetic animals. Nitrosative stress constitutes another mechanism involved in diabetic embryopathy and placental damage. Indeed, our studies have shown elevated nitric oxide production and increased peroxynitrite formation in embryos, fetuses and placentas from diabetic experimental models. In those tissues, the generation of the potent oxidant peroxynitrite impairs the morphogenic role of NO and leads to direct damaging effects such as protein nitrosylation and impairment of different signaling pathways. Matrix Metalloproteinases (MMPs) are enzymes that degrade the extracellular matrix during remodeling processes and are overexpressed in embryos, fetuses and placentas from diabetic pregnancies. This upregulation is related to the increases in NO, ROS and peroxynitrites and leads to an abnormal intrauterine remodeling pattern. Alterations in the metabolism of arachidonic acid impair the production of several prostaglandins (PGs) involved in developmental processes. PGE2 has been clearly found associated with the process of closure of the neural tube during early organogenesis, and its reduced concentrations are 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 have investigated the effects of dietary treatments with PPAR 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. On the other hand, 15deoxydelta12,14PGJ2 is an anti-inflammatory molecule that activates the nuclear receptor PPARgamma. This prostaglandin is capable of reducing NO and MMPs in embryonic and placental tissues but its concentrations are reduced in maternal diabetes. Activation of PPARs also regulate feto-placental lipid homeostasis, and dietary treatments with PPAR activators were able to prevent alterations in lipid metabolism in the developing fetuses. In conclusion, both the overproduction of pro-inflammatory agents and defects in the production of prostaglandins capable of activating PPARs are believed to play a major role in the induction of embryonic and feto-placental anomalies in maternal diabetes and constitute putative targets for future strategies aiming to prevent maternal diabetes induced developmental defects.