Alcohol consumption in any amount by pregnant women cannot be considered safe for the fetus. Although a causal linkage between the quantity and duration of alcohol consumption, phase of pregnancy and fetotoxic effect has not yet been established, there is no doubt that the risk for the fetus is high and it may lead to Fetal Alcohol Syndrome.
Ethanol metabolism during pregnancy.
The alcohol metabolism of a pregnant woman is much depressed compared with that of a non-pregnant woman, as estrogens largerly inhibit the activity of ADH and ALDH (especially estradiol).
Due to his low molecular weight, alcohol passes swiftly through the placenta and enters the bloodstream of the fetus. Although ADH can be found in a fetal liver from the middle of the third month of pregnancy, a fetus has almost no capacity to break down the alcohol.
How alcohol may harm a developing fetus.
The Fetal Alcohol Syndrome is a pattern of mental and physical defects that can develop in a fetus in association with high levels of alcohol consumption during pregnancy.
SIGNS AND SYMPTOMS.
1)SNC: structural abnormalities (microcephaly, agenesis of corpus callosum, Many infants prenatally exposed to high levels of alcohol show one particular anomaly of the corpus callosum, 2007 , cerebellar hypoplasia); neurological problems (epilepsy, neurosensory hearing loss, poor gait, clumsiness, poor coordination); cognitive deficits, attention and hyperactive problems , social skills.
2)GROWTH DEFICIENCY: defined as below average weight, height or both.
4)RELATED SIGNS (alcohol related birth defects): cardiac (heart murmur that often disappears by one year of age, ventricular or atrial septal defect); skeletal (joints anormalities); renal (horseshoe, aplastic, dysplastic or hypoplastic kidneys); ocular (strabism, optic nerve hypoplasia); ptosis of the eyelid, microophthalmia, cleft lip with or without a cleft palate , webbed neck, short neck, tetralogy of Fallot, coarctation of the aorta, spina bifida, and hydrocephalus.
DISEASE MODELS AND MECHANISMS.
Alcohol prenatal exposure may interfere with development pathways. Here are some studies that suggest how alcohol can alter these processes in a fetus.
A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway, 2011 This article shows some experiments carried out on Drosophila, chosen because of its susceptibility to the developmental toxicity of ethanol.
"A Drosophila model of FAS
Prenatal alcohol exposure can cause FAS, a complex disorder with numerous developmental, morphological and neurological deficits (Jones and Smith, 1973). In this study, we investigated the effects of developmental ethanol exposure in the fruit fly Drosophila melanogaster, and found many features in common with FAS. Flies reared on ethanol-containing food displayed a dose-dependent developmental delay, a small larval CNS, increased developmental mortality and reduced adult size. Developmental ethanol exposure also altered ethanol-responsive behaviors in adult flies. Ethanol-reared flies were hypersensitive to the stimulating effects of ethanol, abnormally resistant to ethanol-induced sedation, and defective in tolerance development, all phenotypes also observed in mammalian FAS models.The phenotypic similarities between our model and mammalian FAS models extend to the specificity of critical periods for ethanol-induced developmental phenotypes. We found that, with the exception of ethanol-induced lethality, all of the phenotypes examined exhibit discrete critical periods. The critical period for ethanol-induced growth delay is during the second and third larval instars. Increased sedation resistance results from exposure during the second larval instar, whereas the tolerance defect maps to the late-third-instar or early-pupal stage. Of all the phenotypes examined, only the ethanol-induced lethality is cumulative, increasing in severity with longer exposure times. As with developmental ethanol studies in other organisms, these data indicate that the critical periods of ethanol sensitivity vary depending on what is being measured, i.e. viability versus developmental delay (Blader and Strahle, 1998; Oxendine et al., 2006). Such differences undoubtedly reflect the effects of ethanol on specific developmental events or processes. For example, in the case of the ethanol-induced growth delay, the critical period is a time of rapid cell division and growth in the larva. Our investigations show that ethanol exposure during this growth period interferes with cell division in the brain and imaginal discs (Fig. 3; supplementary material Fig. S7). Therefore, one explanation for the observed phenotypes is that insufficient cellular proliferation leads to delayed growth. Indeed, it is known that reduced cell proliferation in the imaginal discs can cause developmental delay (Brogiolo et al., 2001; Stieper et al., 2008). Taken together, these data suggest that reduction in imaginal disc size explains the ethanol-induced developmental delay.The ethanol-induced defect in tolerance development is particularly interesting, because, unlike the other phenotypes examined, its critical period (late third instar to pupation) is during periods of neuronal differentiation, outgrowth and remodeling, rather than intense cell division. This might indicate that normal development of tolerance is dependent on neurite outgrowth and axon targeting, both of which depend on insulin signaling (Scolnick et al., 2008; Song et al., 2003).Insulin signaling is reduced in flies reared in ethanol
Our studies show that, as in mammals, developmental ethanol exposure in flies leads to diminished insulin signaling. Expression of dilp2 and InR was reduced in the brains of larvae reared on ethanol, and the growth and viability phenotypes were rescued by transgenic supplementation with several Dilps. Similarly, Dilp overexpression rescued the sedation sensitivity and tolerance defects of adult flies subjected to developmental ethanol exposure.It is interesting to note that ubiquitous overexpression of dilp2 was required to rescue viability and developmental delay, whereas overexpression of dilp2 in the brain rescued only the adult behavioral phenotypes of ethanol-reared animals. By contrast, expression of dilp6 in the brain (driven by dilp2-GAL4) was sufficient to rescue both the growth and viability defects, as well as sedation resistance. Although it is possible that the differences are a result of lower expression of the UAS-dilp2 transgene relative to UAS-dilp6, we consider this possibility unlikely because previous studies have found that overexpression of UAS-dilp2 is more effective than UAS-dilp6 to drive increased body size (Ikeya et al., 2002). These results might therefore reveal a previously unidentified specificity of function for dilp2 in regulating behavior when expressed in the brain. Alternatively, it is possible that dilp2 is less efficiently transported from the CNS to other tissues or has lower affinity for InR, such that CNS-specific expression is insufficient to rescue the imaginal-disc-mediated growth and viability defects.Although our results with manipulations of the insulin pathway are satisfying as validation of our model system, they also suggest a potential mechanism for the adult behavioral phenotypes caused by developmental ethanol exposure. In the Drosophila eye, InR is required for proper photoreceptor axon guidance (Song et al., 2003). Similarly, IGF-I is a chemoattractant for axon growth cones in cultured rodent neurons, and IGF signaling is required for proper targeting of axons in the rodent olfactory bulb (Scolnick et al., 2008). It is reasonable to hypothesize that some or all of the behavioral defects caused by developmental ethanol exposure (and that are rescued by Dilp supplementation) are a result of improper neurite outgrowth and/or axon targeting during development. In Drosophila, it is possible to test this hypothesis in a relatively straightforward manner. For example, developmental exposure to ethanol results in increased ethanol-induced locomotion. It is known that a specific pair of dopaminergic neurons in the fly brain mediates ethanol-induced hyperactivity (Kong et al., 2010); similarly, neurons in the pars intercerebralis and central complex have been implicated in sensitivity to ethanol-induced sedation (Rodan et al., 2002). We will be able to examine the general organization of these brain regions using GFP driven by specific GAL4 lines. Analysis of detailed axon pathfinding could then be focused to the relevant neurons using the MARCM technique (Lee and Luo, 2001). We can therefore use this model to investigate the requirement for insulin signaling in the development of the nervous system and how it impacts adult behavior.Potential significance for FAS
Our results in Drosophila and those of McGough and colleagues in rats (McGough et al., 2009) demonstrate that some of the deleterious effects of developmental ethanol exposure can be ameliorated by replacing lost insulin signaling. These results are important because they illustrate the potential for pharmacological intervention in FAS.Despite decades of public awareness campaigns and widespread understanding that alcohol consumption during pregnancy can result in birth defects, the rate of alcohol abuse during pregnancy remains unchanged (Sampson et al., 1997). This is probably due in large part to the addictive effects of alcohol, and highlights the need for alternative solutions to the problem of prenatal ethanol exposure.It is clear from human epidemiological data that genetic factors can modulate the teratogenic effects of alcohol. Monozygotic twins from alcohol-abusing mothers display concordance for FAS defects, whereas dizygotic twins do not (Christoffel and Salafsky, 1975; Streissguth and Dehaene, 1993). Moreover, different inbred mouse and chick strains, in which the timing of alcohol administration and blood alcohol concentration was controlled for, differ in their susceptibilities to ethanol teratogenesis (Boehm et al., 1997; Bupp Becker et al., 1998; Su et al., 2001). It is likely that many genes, in addition to those involved in insulin signaling, confer risk or protection from alcohol injury, yet none have been conclusively identified. Furthermore, insulin supplementation does not rescue the learning and memory defects of the disease, which are the most devastating symptoms of FAS (McGough et al., 2009), indicating the existence of other important developmental targets of ethanol.The molecular identification of genetic factors that influence developmental ethanol toxicity has been hindered largely by the difficulty of performing unbiased, forward genetic screens in vertebrate systems, and it is here that our model is most useful. Our demonstration of both phenotypic and molecular conservation of developmental ethanol effects between flies and mammals indicates that Drosophila is a good model for further elucidation of the mechanisms of action of developmental ethanol exposure. This, in turn, will allow the identification of novel pharmacological targets to prevent/ameliorate the development of FAS."
Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome, 1996 In this article researchers suggest that a pathway inhibited by alcohol could be the retinoic acid pathway because the rate-limiting step in RA synthesis is the oxidation of retinol, a reaction that can be catalyzed by alcohol dehydrogenase (ADH) and ethanol is also a substrate for ADH, and high levels of ethanol inhibit ADH-catalyzed retinol oxidation. In particular they claim that RA deficit is linked to severe craniofacial abnormalities seen in FAS.
Modulation by the GABA receptor siRNA of ethanol-mediated PKA-α, CaMKII, and p-CREB intracellular signaling in prenatal rat hippocampal neurons, 2011
Abstract: Fetal alcohol syndrome (FAS) is a developmental neuropathology resulting from in utero exposure to ethanol; many of ethanol’s effects are likely to be mediated by the neurotransmitter γ-aminobutyric acid (GABA). We studied modulation of the neurotransmitter receptor GABABR and its capacity for intracellular signal transduction under conditions of ethanol treatment (ET) and RNA interference to investigate a potential role for GABA signaling in FAS. ET increased GABAB1R protein levels, but decreased protein kinase A-α (PKA-α), calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation of cAMP-response element binding protein (p-CREB), in cultured hippocampal neurons harvested at gestation day 17.5. To elucidate GABAB1R response to ethanol, we observed the effects of a GABABR agonist and antagonist in pharmacotherapy for ethanol abuse. Baclofen increased GABABR, CaMKII and p-CREB levels, whereas phaclofen decreased GABABR, CaMKII and p-CREB levels except PKA-α. Furthermore, when GABAB1R was knocked down by siRNA treatment, CaMKII and p-CREB levels were reduced upon ET. We speculate that stimulation of GABAB1R activity by ET can modulate CaMKII and p-CREB signaling to detrimental effect on fetal brain development.
Estimating the prevalence of fetal alcohol syndrome. A summary, 2001
Prevalence of children with severe fetal alcohol spectrum disorders in communities near Rome, Italy: new estimated rates are higher than previous estimates, 2011
Alcohol is the leading known preventable cause of developmental and physical birth defects in the United States. When a woman drinks alcohol during pregnancy, she risks giving birth to a child whit FAS. Many pregnant women do drink alcohol. It's estimated that each year in the United States, 1 in every 750 infants is born with a pattern of physical, developmental, and functional problems referred to as fetal alcohol syndrome (FAS), while another 40,000 are born with fetal alcohol effects (FAE). FAS can be completely prevented by not drinking any alcohol during pregnancy.