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Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos

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      Abstract

      OBJECTIVES: It has recently been suggested that oxygen free radicals are involved in the high incidence of fetal dysmorphogenesis that is associated with diabetic pregnancies. The purpose of the current investigation was to study the effect of copper zinc superoxide dismutase, a free radical scavenging enzyme, on the prevention of diabetes-associated embryopathy in mice.
      STUDY DESIGN: Mice used in this study were either transgenic, bearing the human copper zinc superoxide dismutase gene, or nontransgenic controls. Diabetes was generated by streptozotocin administration on days 6 and 7 of gestation. Hyperglycemia developed on day 8 and was maintained through day 10 (critical period of organogenesis). On day 10 fetuses were examined for external anomalies, and their crown-rump lengths and deoxyribonucleic acid content were determined. RESULTS: Induction of maternal diabetes produced a significant reduction in mean crown-rump length of control embryos (4.48 ± 0.7 mm vs 3.65 ± 0.6 mm, p = 0.0001), whereas trangenic embryos were not affected (4.72 ± 0.6 mm vs 4.45 ± 0.8 mm, p > 0.05). After induction of diabetes fetal loss and malformation rates were significantly higher in control embryos (6.0% vs 23.8% and 8.4% vs 16.5%, respectively). Transgenic embryos were practically unaffected by diabetes and showed fetal loss and malformation rates of 5.9% and 4.4%, respectively, after induction of diabetes.
      CONCLUSIONS: Elevated levels of copper zinc superoxide dismutase, a key enzyme in the metabolism of free oxygen radicals, elicit a protective effect against diabetes-associated embryopathy.

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      References

        • Reece EA
        • Gabrielli S
        • Abdalla M
        The prevention of diabetes associated birth defects.
        Semin Perinatol. 1987; 12: 292-296
        • Gabbe SG
        Gestational diabetes mellitus.
        N Engl J Med. 1986; 315: 1025-1026
        • Eriksson U
        • Dahlstrom E
        • Larsson KS
        • Hellerstrom C
        Increased incidence of congenital malformations in the offspring of diabetic rats and their prevention by maternal insulin therapy.
        Diabetes. 1982; 31: 1-6
        • Hanson U
        • Persson B
        • Thunell S
        Relationship between hemoglobin A1c in early type I (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformations in Sweden.
        Diabetologia. 1990; 33: 100-104
        • Sadler TW
        • Hunter III, ES
        • Wynn RE
        • Phillips LS
        Evidence for multifactorial origin of diabetes-induced embryopathies.
        Diabetes. 1989; 38: 70-74
        • Reece EA
        • Pinter E
        • Leranth CS
        • et al.
        Ultrastructural analysis of malformations of the embryonic neural axis induced by hyperglycemia conceptus culture.
        Teratology. 1985; 32: 363-373
        • Cagliero E
        • Forsberg H
        • Sala R
        • Lorenzi M
        • Eriksson UJ
        Maternal diabetes induces increased expression of extracellular matrix components in rat embryos.
        Diabetes. 1993; 42: 975-980
        • Wolff SP
        Diabetes mellitus and free radicals.
        Br Med Bull. 1993; 49: 642-652
        • Gillery P
        • Monboisse JC
        • Maquart FX
        • Borrel JP
        Does free oxygen radical increased formation explain long term complications of diabetes mellitus?.
        Med Hypotheses. 1989; 29: 47-50
        • Fridovich I
        Oxygen radicals, hydrogen peroxide, and oxygen toxicity.
        in: Pryor WA Free radicals in biology. Academic Press, Orlando1976: 239-277
        • Eriksson UJ
        • Borg LAH
        Diabetes and embryonic malformations: role of substrate-induced free-oxygen radical production in dysmorphogenesis in cultured rat embryos.
        Diabetes. 1993; 42: 411-419
        • Eriksson UJ
        • Borg LAH
        Protection by free oxygen radical scavenging enzymes against glucose induced embryonic malformations in vitro.
        Diabetologia. 1991; 34: 325-331
        • Epstein CJ
        • Avraham KB
        • Lovett M
        • et al.
        Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome.
        in: 4th ed. Proc Natl Acad Sci U S A. 84. 1987: 8044-8048
        • Minc-Golomb D
        • Knobler H
        • Groner Y
        Gene dosage of CuZnSOD and Down's syndrome: diminished prostaglandin synthesis in human trisomy 21, transfected cells and transgenic mice.
        EMBO J. 1991; 10: 2119-2124
        • Beauchamp C
        • Fridovich I
        Superoxide dismutase: improved assays and an assay applicable to acrylamide gels.
        Anal Biochem. 1986; 44: 276-287
        • Milles JL
        Malformations in infants of diabetic mothers.
        Teratology. 1982; 25: 385-394
        • Eriksson UJ
        • Borg LAH
        • Hagay Z
        • Groner Y
        Increased superoxide dismutase (SOD) activity in embryos of transgenic mice protects from the teratogenic effects of a diabetic environment.
        Diabetes. 1993; 42: 85A
        • Hunt JV
        • Dean RT
        • Wolff SP
        Hydroxyl radical production and autooxidative glycosylation.
        Biochem J. 1988; 56: 205-212
        • Yang X
        • Borg LAH
        • Eriksson UJ
        Altered mitochondrial morphology in embryos subjected to a diabetic environment.
        Anat Rec. 1994; 241: 255-267
        • Warso MA
        • Lands WEM
        Lipid peroxidation in relation to prostacyclin and thromboxane physiology and pathophysiology.
        Br Med Bull. 1983; 39: 277-280
        • Goldman AS
        • Baker L
        • Piddington R
        • et al.
        Hyperglycemia induced teratogenesis is mediated by a functional deficiency of arachidonic acid.
        in: 4th ed. Proc Natl Acad Sci U S A. 82. 1985: 31
        • Hod M
        • Star S
        • Passonneau JV
        • Unterman TG
        • Freinkel N
        Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis.
        Biochem Biophys Acta Res Commun. 1986; 140: 974-980
        • Pinter E
        • Reece EA
        • Leranth CZ
        • et al.
        Arachidonic acid prevents hyperglycemia-associated yolk sac damage and embryopathy.
        Am J Obstet Gynecol. 1986; 155: 691-702
        • Emerit J
        • Pelletier S
        • Likforman J
        • Pasquier C
        • Thuillier A
        Phase II trial of copper zinc superoxide dismutase (CuZn-SOD) in the treatment of Crohn's disease.
        Free Radic Res Commun. 1991; 12–13: 563-569
        • Thomson PD
        • Till GO
        • Wooliscroft JO
        • Smith DJ
        • Prasad LK
        Superoxide dismutase prevents lipid peroxidation in burned patients.
        Burns. 1990; 16: 406-408