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Antioxidants and Fetal Protection Against Ethanol Teratogenicity. Review of Experimental Data

Antioxidants and Fetal Protection Against Ethanol Teratogenicity. Review of Experimental Data. Raanan Cohen-Kerem Gideon Koren. Outline. Introduction Alcohol as an oxidant Studies review Cell culture Animal models Conclusions . Introduction.

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Antioxidants and Fetal Protection Against Ethanol Teratogenicity. Review of Experimental Data

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  1. Antioxidants and Fetal Protection Against Ethanol Teratogenicity.Review of Experimental Data Raanan Cohen-Kerem Gideon Koren FACE, Sep 2002

  2. Outline • Introduction • Alcohol as an oxidant • Studies review • Cell culture • Animal models • Conclusions FACE, Sep 2002

  3. Introduction • Heavy drinking during pregnancy can result in serious adverse outcomes for the fetus • Fetal Alcohol Syndrome (FAS) • pre and/or postnatal growth retardation • central nervous system damage • typical facial dysmorphology • Incidence of FAS -0.97/1000 a year • 50% of women in childbearing age consume alcohol FACE, Sep 2002

  4. Introduction • The fetus is more susceptible to ethanol than the mother • Ethanol affects biochemical processes and cellular structures through various mechanisms and most of them are still far from being completely understood FACE, Sep 2002

  5. Mechanisms of ethanol induced damage • Amino acid activated ion channels NMDA GABA • Hypoxia • FAEE • Retinoic acid • L1 neural cell adhesion molecule • Endocrine • Oxidative stress FACE, Sep 2002

  6. Objective • To review the data of antioxidant effects in experimental models of fetal alcohol syndrome Treatment with antioxidants in pregnant alcoholic women may potentially prevent ethanol teratogenicity FACE, Sep 2002

  7. CH3-CH-OH (Hydroxyethyl) Direct + - Indirect - How does oxidative stress occur? Peroxidation of lipids, nucleic acids, and proteins + Reactive oxygen species (ROS) + + OH (Hydroxyl) CYP2E1 + Mitochondrial Damage C2H5.OH (Ethanol) Mitochondria Glutathione pool Glutathione peroxidase activity FACE, Sep 2002

  8. Antioxidants • Endogenous • superoxide dismutase • glutathione peroxidase • catalase • Exogenous • Vitamins Vitamin C Tocopherols b-Carotene Folic acid FACE, Sep 2002

  9. Literature Search • Databases: • MEDLINE • EMBASE • Keywords: pregnancy, ethanol, fetus, antioxidants, animal • Included were reports on pregnancy outcome of cell culture or animal FAS model supplemented with antioxidants FACE, Sep 2002

  10. In the lab FACE, Sep 2002

  11. Vitamin E and beta-carotene protect against ethanol combined with ischemia in an embryonic rat hippocampal culture model of FAS Mitchell, Neurosci Lett 263:1999 ; Alcohol 17:1999. • Reduced levels of cytochrome c oxidase mRNA Kim et al, 2001 • Dose-dependent decreased viability of hippocampal cell cultures FACE, Sep 2002

  12. Vitamin E and beta-carotene protect against ethanol combined with ischemia in an embryonic rat hippocampal culture model of FAS Mitchell, Neurosci Lett 263:1999 ; Alcohol 17:1999. • Nutritional supplementation • Vitamin E • b-Carotene • Limitations • Oxidative stress measures • Cells were exposed to ethanol in culture but not in vivo FACE, Sep 2002

  13. Effect of ethanol on rat fetal hepatocytes: studies on cell replication, lipid peroxidation and glutathione Devi, Hepatology18:1993 • 2.0mg/ml ethanol (~1/10 of Mitchell’s study) • Outcome measure: cell replication • Glutathione • Antioxidants: • N-acetylcysteine • S-adenosylmethionine • Vitamin E FACE, Sep 2002

  14. In the lab FACE, Sep 2002

  15. FAS in rats: conditions for improvement of ethanol effects on fetal cerebral development with supplementary agents Tanaka,Biol Neonate 54:1988. • Pregnant rats were fed 20% ethanol +0.03% vit. E, or 10% ethanol + 0.02% vit. E • Outcome measures: • body • cerebral weights • The investigation failed to show protective effect of vit. E FACE, Sep 2002

  16. Protective effects of the flavonoid mixture, silymarin, on fetal rat brain and liver La Grange, J Ethnopharmacol 65:1999. • Antioxidant: Flavonoids (sylibum marianum) • Silymarin-Phytosome • Outcome measure • Tissue GGT activity in embryonic liver and brain FACE, Sep 2002

  17. Protective effects of the flavonoid mixture, silymarin, on fetal rat brain and liver La Grange, J Ethnopharmacol 65:1999. • Limitation • No oxidative stress measures to correlate FACE, Sep 2002

  18. Fetoprotectivity of the flavanolignan compound siliphosagainst ethanol-induced toxicity Edwards, Phytother Res 14 :2000. • Antioxidant: Sylibin • Outcome measures • Fetal survival • GGT activity in the embryonic brain and liver • Glutathione (GSH) activity in the embryonic brain and liver FACE, Sep 2002

  19. Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats Reid, Planta Med 65:1999. • Antioxidant: Silymarin • Outcome measure • social recognition score of the offspring was obtained in two periods of 5 minutes separated by 60 minutes interval • Limitations • No oxidative stress measures to correlate FACE, Sep 2002

  20. Fetal Body Weight Protective effect of folic acid against oxidative stress produced in 21- day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period Cano, Free Radic Res34:2001. • Antioxidant: Folic acid 152mg/day • Outcome measures • Body weight • Glutathione reductase in the fetal liver & pancreas • Carbonyl group proteins FACE, Sep 2002

  21. Protective effect of folic acid against oxidative stress produced in 21- day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period Cano, Free Radic Res34:2001. Fetal glutathione reductase *-ethanol vs. control and vs.ethanol+FA Fetal carbonyl groups FACE, Sep 2002

  22. FACE, Sep 2002

  23. Alpha-tocopherol and gamma-tocopherol attenuate ethanol-induced changes in membrane fatty acid composition in embryonic chick brains Miller, Teratology 62 :2000. • Injection of ethanol with or without vitamin E • Outcome measure: • long chain membrane fatty acids in brain tissue • Brain mass FACE, Sep 2002

  24. Alpha-tocopherol and gamma-tocopherol attenuate ethanol-induced changes in membrane fatty acid composition in embryonic chick brains Miller, Teratology 62 :2000. • Reduction in stearic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid • Reduction in brain mass • Supplementation of vitamin E prevented these effects and maintained brain mass FACE, Sep 2002

  25. Discussion • A protective effect of antioxidants against ethanol-induced damage is observed in the available animal studies • Can we apply this prophylactic treatment to pregnant women? FACE, Sep 2002

  26. Lancet 1999; 354: 810-16 Discussion • Applying antioxidant treatment in pregnancy is not a new concept • Antioxidants (Vitamins E & C) for pre-eclampsia • These antioxidants were not found to be teratogenic FACE, Sep 2002

  27. Conclusions • Oxidative stress is a principal mechanism of ethanol induced damage • Ethanol induced fetotoxicity was shown to be reduced by antioxidants in cell cultures and animal models • Data regarding these effects in human are not available yet FACE, Sep 2002

  28. Take home message • Treating women who abuse alcohol during pregnancy with antioxidants by food supplements as vitamins is appealing: • It may hold a protective effect against FAS as shown in the reviewed studies • it may reverse other nutritional deficits common in this population FACE, Sep 2002

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