Developmental toxicity--magnitude of the problem.
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Abnormalities, Drug-Induced↗
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Results for “Fetal Alcohol Spectrum Disorders”
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[Gamma-glutamyltransferase in maternal serum and prenatal screening for the fetal alcohol syndrome].
In order to investigate prospectively in pregnant women a correlation between serum levels of a biological marker of alcohol and the clinical status of the newborn, we measured the gamma-glutamyltransferase (GGT) in 630 women between 14 and 20 weeks of pregnancy. In 7% of the cases, an elevated value was observed while history confirmed alcohol consumption in only 1%. Preliminary statistical analysis established upon the blind examination of 308 newborns show a correlation between maternal GGT levels and birthweight as well as the pre- and perinatal complications. However, the sensitivity of this test is weak.
Female↗
Biochemical and morphologic effects of ethanol on fetuses from normally ovulating and superovulated mice.
To further our understanding about the teratogenicity of ethanol, we studied the changes produced by this compound in the incorporation of glucose 14C into several tissue fractions of 12-day mice fetuses and the morphologic alterations present at day 19 of gestation. Furthermore, to determine if the fetal toxicity of ethanol was modified by changes in the characteristics of the pregnancy, we performed similar biochemical and morphologic observations in fetuses from superovulated mice. Maternal ethanol administration caused biochemical alterations in the fetal tissues of both normally ovulating and superovulated mice, but it caused morphologic alterations predominantly in fetuses from superovulated animals. The prevalent morphologic alteration found in ethanol-treated animals was a hemorrhagic lesion dorsal to the lumbar or dorsal vertebrae. These results suggest that superovulation increases the susceptibility of the fetal mice tissues to the teratogenic effects of ethanol.
Abnormalities, Drug-Induced↗
Effect of maternal ethanol consumption during pregnancy on the phospholipid molecular species composition of fetal guinea-pig brain, liver and plasma.
The effect of maternal ethanol consumption during pregnancy upon accumulation of docosahexaenoic acid (22:6(n - 3)) into developing brain phospholipids was determined in a guinea-pig model of fetal alcohol syndrome. Feeding adult guinea-pigs 6 g/kg per day ethanol both before and throughout pregnancy was associated with decreased 22:6(n - 3) concentration in both fetal brain phosphatidylcholine (PC) and phosphatidylethanolamine (PE) at 40/68 days gestation and at term. Since adequate assimilation of 22:6(n - 3) into fetal brain is critical for optimal neuronal development, reduced accumulation of 22:6(n - 3) into phospholipids may be one important mechanism for ethanol-induced brain damage. Liver from ethanol-exposed fetuses contained significantly lower concentrations of both PC and PE 22:6(n - 3)-containing molecular species. However, there was no difference in plasma PC polyunsaturated fatty acid content in ethanol-exposed fetuses compared with controls. One possible explanation for impaired 22:6(n - 3) accumulation into ethanol-exposed fetal brain phospholipids may be the result of the action of inappropriate mechanisms which counteract ethanol-induced increased membrane fluidity by reducing the polyunsaturated fatty acid content of brain phospholipids.
Alcohol Drinking↗
Infants of drug-dependent mothers.
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Abnormalities, Drug-Induced↗
Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 1. Teratogenicity of ethanol and acetaldehyde.
The proximate teratogen of the fetal alcohol syndrome is unknown. CD-1 mice were treated ip on Day 10 of gestation with 2, 4, 6, or 7 g/kg ethanol. The percentage of resorptions and malformed fetuses was increased and mean fetal weight was decreased in a dose-related manner. Treatment with 7 g/kg ethanol ip on one of gestational Days 7, 8, 9, 10, or 11 significantly increased the percentage of malformed fetuses and decreased fetal weight. In addition, treatment on Days 10 or 11 significantly increased the percentage of resorptions. Coadministration of 100 mg/kg of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, orally with 6 g/kg ethanol ip on Day 10 of gestation dramatically increased the embryotoxicity of ethanol. Five ip treatments of 200 mg/kg acetaldehyde at 2-hr intervals on Day 10 of gestation did not significantly increase the percentage of resorptions and malformed fetuses or decrease fetal weight. These data suggest that ethanol is the proximate teratogen of the fetal alcohol syndrome in CD-1 mice.
Abnormalities, Drug-Induced↗
Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 2. Pharmacokinetics of the placental transfer of ethanol and acetaldehyde.
CD-1 mice were treated ip on Day 10 of gestation with 4, 6, or 7 g/kg ethanol. Maternal and embryonic tissues were analyzed for ethanol and acetaldehyde levels by head-space gas chromatography 5 min to 24 hr after treatment. Dose-dependent ethanol concentrations were observed in maternal blood and liver. Ethanol rapidly crossed the placenta and appeared in the embryo 5 min after treatment. Acetaldehyde was detectable in maternal blood following all treatments and in maternal liver and embryos following treatment with 7 g/kg ethanol. Coadministration of 100 mg/kg 4-methylpyrazole, an alcohol dehydrogenase inhibitor, with 4 or 6 g/kg ethanol on Day 10 of gestation significantly reduced the rate of ethanol elimination in all tissues examined. This reduction was manifested as a prolongation in the half-life of ethanol detectable in maternal and embryonic tissues but not in an increase in maximum ethanol concentrations. Within 5 min of maternal ip treatment with 200 mg/kg acetaldehyde on Day 10 of gestation, acetaldehyde was detectable in the embryo. These data suggest that both ethanol and acetaldehyde are accessible to the embryo during a critical period of development.
Acetaldehyde↗
Can methionine and zinc prevent the embryopathic effects of alcohol?
Alcoholism is a major and world-wide health problem. A characteristic pattern of congenital defects, known as the fetal alcohol syndrome, has been detected in the offspring of mothers who are chronic alcoholics. The mechanism underlying the teratogenic effects of ethanol is not known. An important hypothesis is that ethanol becomes teratogenic by inducing maternal/fetal nutritional deficiencies. Nutrients affected by ethanol consumption include methionine and zinc. Epidemiological and experimental studies have shown that zinc deficiency is associated with both fetal growth retardation and developmental defects. Furthermore, the ethanol metabolizing enzyme, alcohol dehydrogenase, is a zinc metalloenzyme. Zinc deficiency decreases alcohol dehydrogenase activity and thus slows down elimination of ethanol. Methionine, an essential amino acid, is a lipotrope, as well as a universal methyl donor. It is involved in hepatic detoxification. Studies on the effects of methionine and zinc might lead to appropriate therapeutic intervention in pregnancies of alcoholic mothers who are at a risk of giving birth to an impaired offspring. Furthermore, the results of such investigations will provide a better understanding of the mechanism of action of ethanol on the embryo.
Animals↗
Teratogenic effects of acetaldehyde in the rat.
Acetaldehyde, the proximal metabolite of ethanol, was administered intraperitoneally in single and triple doses (50, 75, 100 mg/kg) to pregnant CF rats on days 10, 11 and 12 of gestation and fetuses were collected on day 21. Besides significant fetal resorptions, malformations were found which included edema, microcephaly, micrognathia, micromelia, hydrocephaly, exencephaly, hemorrhages etc. Somatometric measurements of fetuses (i.e. crown rump length, transumbilical distance and tail length) revealed significant growth retardation. Alizarin red-stained skeletal preparations showed considerable stunting. The placental weight and umbilical cord length were also significantly reduced. The close similarity of the pattern of acetaldehyde-induced fetal malformations with those resulting from maternal alcohol consumption during pregnancy is suggestive of the possible implication of acetaldehyde in the fetal alcohol syndrome.
Abnormalities, Drug-Induced↗
Acetaldehyde and alcohol levels in pregnant rats and their fetuses.
Alcohol and acetaldehyde blood levels were measured in chronic alcoholic pregnant rats and their fetuses at 15, 19 and 21 days of gestation. Similar ethanol concentrations were found in fetal and maternal blood in all gestation periods studied, however levels in amniotic fluid were higher than in mother's blood, especially in the early stages of gestation. Acetaldehyde concentrations were always lower in fetal than in maternal blood although increasing throughout gestation. The levels in fetal blood and amniotic fluid compared to maternal blood, were ca. 40, 50 and 70% at 15, 19 and 21 days of gestation, respectively; those for the placenta and fetal tissues were lower, i.e., 25, 40 and 50%. Similar alcohol and acetaldehyde ratios (fetus/mother's concentration) were obtained when pregnant non-alcoholic rats were administered cyanamide and ethanol (2 g/kg) at 11, 15, 19 and 21 days of gestation. These results demonstrate that ethanol freely crosses the placental barrier, but there is a concentration gradient of acetaldehyde between mother and fetus which varies with gestation age.
Acetaldehyde↗
Effects of prenatal alcohol exposure in mice: influence of an ADH inhibitor and a chronic inhalation study.
In order to examine the effects of an alcohol dehydrogenase inhibitor on the embryotoxic effects of ethanol, pregnant ICR mice were treated with 100 mg/kg pyrazole prior to ethanol injection. I.p. treatment with 2 or 4 g/kg ethanol on day 7 of gestation increased the prenatal mortality rate and produced external and skeletal malformations in the offspring, and the embryotoxic effects were potentiated by pyrazole pretreatment, suggesting that ethanol rather than its metabolites is mainly responsible for the embryotoxicity. In the second experiment, we housed pregnant mice in an ethanol-vapor box for 3 or 6 days in order to examine the effects of prolonged low level exposure to alcohol. The maternal blood alcohol concentration was maintained approximately 0.03 mg/mL during inhalation. The inhalation treatment with ethanol increased the prenatal mortality rate, although teratogenicity was not shown.
Abnormalities, Drug-Induced↗
Prevention of alcohol-induced developmental delays and learning abnormalities in a model of fetal alcohol syndrome.
OBJECTIVE: Prenatal alcohol exposure results in fetal death and neurobehavioral complications including learning impairment. Previously synthetic peptides derived from activity-dependent neurotrophic factor have been shown to prevent aspects of alcohol-induced damage in pregnancy. The objective of this work was to evaluate whether activity-dependent neurotrophic factor-12 could prevent alcohol-induced damage in a model of fetal alcohol syndrome. STUDY DESIGN: Using a well-characterized model, C57Bl6/J mice on gestational day 8 were treated with placebo, alcohol (30% volume/volume alcohol 0.03 mL/kg), alcohol plus activity-dependent neurotrophic factor-12 30 minutes prior to alcohol, or activity-dependent neurotrophic factor-12 alone. Fetal death was assessed on gestational day 18 (25 litters were evaluated: alcohol, n = 5; placebo, n = 9; alcohol plus activity-dependent neurotrophic factor-12, n = 11). Neonatal behavior tests were performed on postnatal days 1 through 21 with the offspring of 12 dams (alcohol, n = 16; placebo, n = 46; alcohol plus activity-dependent neurotrophic factor-12, n = 23; and activity-dependent neurotrophic factor-12, n = 35). Adult males were tested in the Morris water maze for learning assessment and with the hole punch activity test for exploratory activity. Statistical analysis included Kruskal-Wallis and analysis of variance. RESULTS: Fetal death was greater in alcohol (67% +/- 13%) vs placebo (8.4% +/- 3%, P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced fetal death (2.2% +/- 8.1%) with levels similar to control (P = .12). Alcohol exposure caused a delay in achieving developmental milestones, with alcohol achieving milestones later than all other groups (all P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced milestone delays. In the Morris water maze, the placebo learned, decreasing their latency to find the hidden platform over 70% (P < .01). Alcohol plus activity-dependent neurotrophic factor-12 also significantly learned, with a learning curve not different from placebo (all P > .5) and significantly better than alcohol on days 4, 6, and 7 (all P < .05). Alcohol exposure resulted in significantly less time in hole punch activity (P < .02) than control. Activity-dependent neurotrophic factor-12 pretreatment prevented the alcohol-induced decline, with levels the same as control (P = .1). CONCLUSION: The novel peptide activity-dependent neurotrophic factor-12 prevents alcohol-induced fetal death and developmental and learning abnormalities in a model of fetal alcohol syndrome. This demonstrates that a single treatment with a peptide is efficacious and may be of value in the prevention of alcohol-induced damage.
Animals↗
Gene-expression analysis after alcohol exposure in the developing mouse.
Exposure to alcohol in the embryonic mouse can lead to structural and neurophysiologic changes. The cause of these changes is poorly understood, but they are likely the result of numerous mechanisms. Here we investigate ethanol-induced alterations in gene expression in the fetal brain. Using complementary-DNA microarrays, we identified 25 genes that were down-regulated by prenatal ethanol exposure on days 7 and 9 of gestation. None were found to be up-regulated. Of those that were repressed, 6 (Timp4, Bmp15, Rnf25, Akt1, Tulp4, Dexras1) have been identified, and they are discussed here in the context of the developing fetus. The identified genes have been shown to be involved in cell proliferation, differentiation, and apoptosis, and they contribute to tissue growth and remodeling, as well as neuronal growth and survival. Microarray studies may be useful in the identification of a genetic marker for fetal alcohol syndrome, the discovery of novel pathways that may be involved in its origin, or both.
Animals↗
A critical role of Pax6 in alcohol-induced fetal microcephaly.
Maternal alcohol abuse during pregnancy is one of the leading causes of birth defects in humans. Despite extensive studies, the molecular basis is still not clear. Here we transiently exposed Xenopus embryos to alcohol and showed that alcohol dose-dependently produced microcephaly and growth retardation. Moreover, it reduced the expression of several key neural genes (xPax6, xOtx2, xSox3, xSox2, and xNCAM), of which xPax6 was most vulnerable. An alcohol concentration as low as 0.3% could produce more than 90% reduction of xPax6 expression. Consistently, microinjection of xPax6 expression plasmid to Xenopus embryos dose-dependently rescued alcohol-induced microcephaly and restored the expression of xOtx2, xSox3, xSox2, and xNCAM. To test whether reactive oxygen species (ROS) is the upstream signal for alcohol-induced microcephaly and xPax6 suppression, we overexpressed catalase in Xenopus embryos and found that catalase not only decreased alcohol-induced H(2)O(2) formation, but also fully restored Pax6 expression and reversed microcephaly. In contrast, xPax6 and catalase could only provide partial protection against growth retardation. Results from this study illustrate for the first time the critical role of H(2)O(2)-mediated Pax6 suppression in alcohol-induced microcephaly and suggest the presence of additional mechanisms for alcohol-induced fetal growth retardation.
Animals↗
Ethanol exposure during development reduces resident aggression and testosterone in rats.
Ethanol exposure during development has been shown to alter social behaviors in people, but the range of deficits is not clear. Using an animal model of Fetal Alcohol Spectrum Disorders, inter-male aggression and testosterone levels were examined in adult rats. Rats were exposed to ethanol during the entire prenatal period and from postnatal day 2 through 10. Ethanol was administered via intragastric intubation. Two other groups consisted of a nontreated control and an intubated control group that was exposed to the administration procedures but not ethanol. Both offensive and defensive aggression were examined in experimental residents and intruders under three different housing conditions for the resident males: (1) with another male, (2) with a pregnant female, and (3) with a female and litter fathered by the experimental animal. When housed with a female and litter, ethanol-exposed rats displayed reduced offensive aggression compared to control groups under the same condition. Defensive aggression in the non-experimental intruders was reduced in this same condition. There were no differences in duration of non-aggressive social behaviors among the groups in any of the housing conditions. Testosterone levels were reduced in ethanol-exposed rats compared to controls. In summary, ethanol exposure over the combined prenatal and postnatal periods reduces aggressive behavior in a condition where aggressive behavior is normally seen. This reduction may be related to lower testosterone levels.
Aggression↗
Cerebral oxidative metabolism in fetal sheep with multiple-dose ethanol infusion.
Cerebral oxidative metabolism and cotylendonary blood flow were measured in 10 unanesthetized fetal sheep (127 to 132 days' gestation) during a control period, after the first, third, and fourth infusions of four doses of 0.5 gm of ethanol per kilogram of maternal body weight infused into the ewe during 5 hours, and 24 hours after ethanol infusion. Preductal arterial and sagittal vein blood samples were analyzed for oxygen content, blood gases, pH, and ethanol. Cerebral and cotylendonary blood flow were measured with a radioactive microsphere technique. Fetal blood gases and pH changed little with the ethanol infusions, although PaO2 and oxygen content decreased 24 hours after ethanol infusion. Cotylendonary blood flow, which was decreased after the third and fourth ethanol infusions, did not account for these delayed hypoxemic changes. Similarly, cerebral oxidative metabolism was decreased when measured after each of the ethanol infusions, with no dose response or tolerance evident. This noted fall in fetal cerebral oxidative metabolism appears to be a direct depressant effect that was maximal at rather low fetal ethanol levels, which, if prolonged, might well affect cerebral growth and development. Recovery of cerebral metabolic function appeared complete by 24 hours. However, relative fetal hypoxemia was evident at this time, the mechanism of which remains to be determined.
Animals↗
The effects of acute alcohol intoxication on biophysical activities: a case report.
A computer-assisted biophysical assessment was performed in a woman with chronic alcoholism at 37 weeks' gestation. She was first seen in a state of acute alcohol intoxication (322 mg/dl). Although fetal breathing movement incidence was normal (30%), fetal tachypnea (67 breaths per minute) and decreased fetal body movements (0.11%) were seen. Because these findings differ from those previously reported with regard to normal pregnancies exposed to lower levels of alcohol, their implications are discussed.
Adult↗
Exposure of piglet coronary arterial muscle cells to low alcohol results in elevation of intracellular free Ca2+: relevance to fetal alcohol syndrome.
Chronic exposure of cultured piglet neonatal coronary arterial smooth muscle cells to low concentrations of ethanol (46-115 mg/dl) for 7 days resulted in concentration-dependent elevation in intracellular free Ca2+ ions ([Ca2+i); these rises (22-56%) in [Ca2+]i were not reversible upon short-term exposure to normal, Ca2(+)-containing physiological salt solution. These findings help to provide a rational basis for why ethanol can result in the well-known fetal alcohol syndrome, including cardiac defects and in-utero death.
Animals↗