Transcript Can Antioxidants Protect the Fetus Against Maternal

Antioxidants and Fetal
Protection Against Ethanol
Teratogenicity.
Review of Experimental Data
Raanan Cohen-Kerem
Gideon Koren
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Outline
• Introduction
• Alcohol as an oxidant
• Studies review
- Cell culture
- Animal models
• Conclusions
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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
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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
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Mechanisms of ethanol
induced damage
• Amino acid activated ion channels
• Hypoxia
NMDA
GABA
• FAEE
• Retinoic acid
• L1 neural cell adhesion molecule
• Endocrine
• Oxidative stress
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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
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How does oxidative stress occur?
Peroxidation of lipids,
nucleic acids, and
proteins
+
Reactive oxygen
species (ROS)
CH3-CH-OH
(Hydroxyethyl)
+
OH
Direct
+
CYP2E1
(Hydroxyl)
+
C2H5.OH
(Ethanol)
Mitochondrial
Damage
+
Mitochondria
-
Indirect
-
Glutathione
peroxidase activity
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Glutathione
pool
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Antioxidants
• Endogenous
‫ ־‬superoxide dismutase
‫ ־‬glutathione peroxidase
‫ ־‬catalase
• Exogenous
‫ ־‬Vitamins
Vitamin C
Tocopherols
b-Carotene
Folic acid
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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
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In the lab
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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
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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
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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
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In the lab
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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
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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
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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
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Fetoprotectivity of the flavanolignan compound siliphos
against 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
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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
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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 Res
34:2001.
•
•
Antioxidant: Folic acid 152mg/day
Outcome measures
-
Body weight
Glutathione reductase in the fetal liver & pancreas
Carbonyl group proteins
Fetal Body Weight
Weeks
1st
2nd
3rd
Control
10.72
11.51
9.06
Ethanol
4.93*
7.20*
4.12*
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Ethanol + Folic a
8.25*
7.98*
6.56*
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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 Res
34:2001.
Fetal glutathione reductase
Liver
Pancreas
Control
15.1
14.3
Ethanol
18.8*
14.9
Ethanol + Folic a
16.4
16.0
Ethanol
16.42*
19.63*
Ethanol + Folic a
6.72*
16.15
*-ethanol vs. control and vs.ethanol+FA
Fetal carbonyl groups
Liver
Pancreas
Control
12.48
12.24
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Alpha-tocopherol and gamma-tocopherol attenuate ethanolinduced 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
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Alpha-tocopherol and gamma-tocopherol attenuate ethanolinduced 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
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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?
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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
Lancet 1999; 354: 810-16
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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
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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
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