Role of embryonic mitochondria in the generation of congenital malformations in diabetic pregnancy

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Diabetic pregnancy is associated with an increased incidence of congenital malformations. The teratologicalmechanism may be related to an alteration of embryonic organogenesis by maternal metabolic derangementsduring early gestation. Mitochondria, the site of biological oxidation in the embryo, may be directly affectedby the disturbed maternal metabolism. The embryonic mitochondria may respond to an increased metabolicload by producing an increased amount of free oxygen radicals, which, in diabetic pregnancy, has beensuggested to disturb embryonic morphogenesis. The present study demonstrated that embryonic mitochondriaexposed to maternal diabetes in vivo or to high concentrations of glucose, pyruvate, β-hydroxybutyrate andα-ketoisocaproate in vitro during organogenesis showed a pronounced morphological alteration, a high-amplitude swelling. The swelling of mitochondria was eliminated both in vivo by maternal ingestion of theantioxidants, vitamin E or BHT, and in vitro by inhibition of mitochondrial uptake of excess pyruvate withCHC, thus suggesting that the swelling of embryonic mitochondria was a result of oxidative damage causedby free oxygen radicals produced by the mitochondria themselves. When embryonic neural tissue wasincubated with high concentration of glucose, oxygen uptake of the tissue was inhibited and glucoseutilization was stimulated, indicating a Crabtree effect. The changed metabolic state induced by highconcentration of glucose was associated with a generation of superoxide. Embryos of diabetic rats showed alow oxygen uptake and a low glucose utilization. Superoxide production was undetectable in these embryos,indicating an impaired mitochondrial function. High concentration of β-hydroxybutyrate induced differentmetabolic alterations in embryonic neural tissue during early and late organogenesis. Superoxide generationmight be induced by the ketone body during early organogenesis. Thus, the teratogenic mechanism of theketone body may differ, depending on the time of exposure. An increased frequency of lysosome-likestructurcs was found in the endodermal cells of visceral yolk sac of diabetic rats, which was diminished by anantioxidant-supplemented diet, indicating an involvement of oxidative stress in the formation of suchchanges. The mitochondria in visceral yolk sac were not affected morphologically by diabetes. They showeda well developed structure similar to that in adult tissues. Accordingly, the increased resistance of themitochondria in visceral yolk sac to the adverse effects of diabetes might be related to their greater maturitycompared to that of mitochondria in the embryo proper. A similar resistance was also found in the tissues offetal brain, heart, and liver on gestational day 15. The findings of this study suggest a dual role ofembryonic mitochondria as a producer and a target of free oxygen radicals in the teratological process ofdiabetic pregnancy. The Crabtree effect is proposed as a link between glucose-induced metabolic alterationsand a mitochondrial superoxide production in the embryonic tissue during diabetic pregnancy.

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