Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos.
The aim of this study was to evaluate the role of free-oxygen radicals in the embryonic maldevelopment of diabetic pregnancy. Rat embryos cultured in vitro during early organogenesis showed growth retardation and severe malformations after exposure to 50 mM glucose, 3 mM PYR, 10 mM HBT, or 3 mM KIC. Combinations of 25 mM glucose, 2.5 mM HBT, and 1 mM KIC also elicited embryonic growth retardation and malformations. The deleterious effects on embryonic development by all agents were alleviated by addition of SOD to the culture media, which yielded increased enzyme activity in the embryos and their membranes. The endogenous SOD activity also increased in embryos subjected to a high concentration of glucose or PYR in the culture medium. Addition of the mitochondrial PYR transport inhibitor CHC to the culture media blocked the dysmorphogenesis caused by glucose and PYR, but was without effect on the teratogenic actions of HBT and KIC. These findings implicate the embryonic mitochondria as a likely site for enhanced substrate-induced production of free-oxygen radicals mediating the teratogenic effect of a diabetic environment. In particular, the teratogenic process in diabetic pregnancy may depend on an increased production of free-oxygen radicals in immature embryonic mitochondria in response to a metabolic overload. This notion implies that every oxidative substrate entering the mitochondrial metabolism in excess may induce embryonic malformations and emphasizes the need for an extended metabolic surveillance of pregnant diabetic women. Consequently, optimal metabolic control should aim at normalizing the maternal serum concentrations of all possible oxidative substrates.
Eriksson
U J
UJ
Department of Medical Cell Biology, University of Uppsala, Sweden.
Borg
L A
LA
D020155:3-Hydroxybutyric Acid; D000818:Animals; D000013:Congenital Abnormalities / Q000196:embryology; D046508:Culture Techniques; D004622:Embryo, Mammalian / Q000002:abnormalities*; D005260:Female; D005609:Free Radicals / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006885:Hydroxybutyrates / Q000378:metabolism; D007651:Keto Acids / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley
D005609:Free Radicals; D006885:Hydroxybutyrates; D007651:Keto Acids; D011773:Pyruvates; C013082:alpha-ketoisocaproic acid; D019289:Pyruvic Acid; D005947:Glucose; D010100:Oxygen; D020155:3-Hydroxybutyric Acid