Many studies have established that a developing organism is susceptible to exogenous and endogenous factors during certain stage of the organism’s development. The effects of ethyl alcohol or ethanol on the developing fetus, which manifest a variety of characteristic abnormalities, are collectively called Fetal alcohol Syndrome. Ethanol exposure to the fetus causes various malformation ranging from the cellular to the organismic levels with the eventual results frequently being different levels of mental retardation (3).

Chick embryo studies provide a relatively good model for defining the effects of ethanol at many organizational levels of neurogenesis, cell death, neuronal migration and differentiation, cell to cell connectivity, and synaptic function When ethanol is administered to embryos on days one to three of development, the cholinergic neuronal phenotypes were markedly decreased possibly in the sparing of catecholaminergic phenotypes which were increased. This differential sensitivity of these two early neuroblast populations to ethanol may also reflect the difference in their ontogenesis: cholinergic elements are reported to be expressed as early as the primitive streak, whereas catecholaminergic elements appear later (3).

Embryos on embryonic day one are most susceptible to the effects of ethanol. Embryonic day one in the chick is marked by an active process of neurogenesis and neuro-organization. The neural tube elements are made during this early embryonic period. Brodie and Vernadakis inspected the effect of ethanol on cholinergic spinal cord neurons during this embryonic period. The neuroblast during this period shows plasticity with respect to neurotransmitter phenotypes, when exposed to various environmental factors. Exposure to exogenous elements such as ethanol during this dynamic neuroembryonic period, may interfere with important parameters of neuronal growth such as cell to cell connectivity, neuronal migration and phenotypic expression. The consequences of ethanol are dependent on the time of administration and duration of treatment (3).

Animal models have displayed conclusively that alcohol can alter normal development of the central nervous system. Alcohol exposure during development has been shown to modify brain growth, neuronal number, myelination, neurotransmitter levels and receptor binding, synaptogenesis, and many other aspects of neuronal metabolism and morphology. There are indications of alcohol’s immediate or short term teratogenic effects, typically recounting deficits or delays in brain growth parameters, measured in the animals that were still in early stages of development (2).

Most infants identified with FAS are microcephalic, hyperactive, and mentally retarded by age four to ten. This persistence of brain dysfunction is what causes the highest human and economic toll (2).

Several studies have exhibited reductions in neuronal number in developing animals following alcohol exposure. However, neuronal death is a consequence of normal development. Some neuronal populations maintain a fifty percent reduction in the number before stabilizing in an adult configuration. The possibility exists that developmental alcohol exposure may in at least some circumstances, be accelerating the deaths of only those neurons that were destined to die anyway. Some neuronal populations stay in a proliferative state, not only in the early postnatal period, but well into adulthood as well. Alcohol reductions in neuronal numbers described during development do not guarantee they will last into adulthood. During the early postnatal period, the rat brain consists of some neuronal groups that are post-mitotic and others that are not, thus allowing the long term effects of alcohol on the two types of populations to be compared. The early postnatal stage is a time of rapid brain growth, during which the developing CNS is highly susceptible to a variety of teratogenic influences, including those of ethanol (2).

In the long term effects of development, alcohol exposure may exist among neuronal populations predicted on their time of generation and differentiation, relative to the time of the alcohol exposure, and on their regional location within the CNS. They assimilated the vulnerabilities of neuronal populations which were being generated at the time of exposure (Postnatally derived granule cells of the dentate gyrus and cerebellum) with the vulnerabilities of populations which there post-mitotic and were in the process of differentiation (prenatally derived hippocampal pyramidal neurons and cerebellar Purkinje cells) (2).

In neonatal animals examined directly after the period of alcohol exposure, there was an indication that a smaller total amount of alcohol can actually produce greater brain damage during the brain growth spurt than a larger amount of alcohol, provided that it produces relatively higher peak blood alcohol concentration. The pattern of alcohol consumption may be a danger factor in producing permanent alcohol induce CNS damage (2).

Females may be more susceptible than males to some of the long term consequences of fetal alcohol exposure, including microencephaly and behavioral dysfunction. Gender distinctions in the severity of alcohol induced cell loss may play an important role (2).

Purkinje cells in the neonatal rat are spatially separated across the cerebellar vermis according to size, shape, and maturational states. They have shown that purkinje cells located in areas of early differentiation are most vulnerable to alcohol induced cell death during the early postnatal period than are Purkinje cells located in regions of delayed differentiation (2).

One of the three most common identifiable determinants of mental retardation and neurological abnormalities in the western world is fetal exposure to ethanol. Children with FAS elicit a widely variable symptomatic picture in three areas: 1) growth deficiency, which is usually of prenatal onset and which continues postnatally and is evident both in length and weight of effected fetuses and children: 2) a particular pattern of facial malformations including short palpebral fissures, flat midface, the upper vermillon, hypoplastic philtrum, upturned nose, flat nasal bridge, and epicanthal folds; 3) evidence of central nervous system abnormality, which may include microcephaly, tremulousness, motor problems, developmental delays, hyperactivity and neonatal retardation (4).

The teratogenicity of ethanol ranges from no effect at certain doses at certain times for certain people to embryo lethality under other conditions. A variety of associated symptoms is attributed to alcohol ingestion during pregnancy. FAS may be the most common teratogenic cause of mental retardation in the western world. Between six and eleven thousand children are born each year that include major or minor physical birth defects caused by prenatal alcohol exposure. It is estimated that eight percent of all cases of mild mental retardation are a consequence of prenatal exposure to alcohol. Recent prevalence estimates have suggested the FAS may be the most frequent identifiable cause of mental retardation for children born in the USRR and Europe (4).

Some of the elements related to alcohol’s effects in utero are genetic. The structural deficiencies observed in the brain of three prenatally alcohol exposed child would occur in pattern. This pattern would suggest that the cerebral cortex, corpus callosum, and anterior commissure would be involved by prenatal exposure to alcohol in the first 85 days of gestation This is the stage of most rapid neuronal migration. The neuroglial heterotopia’s and cortical dysgenesis would result from exposure during the second trimester. damage to the cerebral white matter would result from third trimester exposure. Neuropathological alterations in patients with FAS have included most frequently microcephaly, cerebellar dysgenesis, cerebral nuclear dysgenesis, agenesis of the corpus callosum, and neuroglial heterotopia’s, both macroscopic and microscopic. Microscopic heterotopia’s are the most common. Neural tube defects have included lumbosacral myelomeningocele and anencephaly. Few differences have been found between intermittent versus daily alcohol use with respect to morphological abnormalities. A number of animal studies which showed that prolonged exposure to ethanol causes a deficiency of serotonin and 5-HIAA in the cortex, cerebellum, and brainstem (4).

One class of molecules known to have effects on both cellular differentiation and proliferation is the retinoids. Ethanol is a teratogen. A teratogen is an agent that causes birth defects. There is a possible role of retinoids in the teratogenic effects of ethanol. The defects may be morphological, physiological, biochemical, or behavioral. The behavioral effects are often of a more subtle nature and thus may go undetected. FAS is characterized by such things as growth deficiency, altered morphogenesis, and central nervous system dysfunction. Children with only some of these features and a history of gestational exposure to ethanol are diagnosed with fetal alcohol effects. Behavioral, neurological, and functional deficiencies have likewise been displayed in offspring of alcoholics. These manifestations of central nervous system dysfunction include retarded mental and motor development, hyperactivity, respiratory distress, fine motor dysfunction, tremulousness, poor hand/eye coordination, poorly organized sleep-wake states, hyperacusis, jitteriness, abnormal electroencephalograms, seizures, poor sucking behavior, and delayed developmental milestones. The mechanism by which ethanol produces its teratogenic effects have included abnormal prostaglandin metabolism, chromosomal alterations, placental dysfunction, hypoxia, interference with protein synthesis, altered growth signaling, interference with neurotransmitter production which can lead to neuroendocrine abnormalities, and alteration of enzymes which regulate glycogen synthesis and degradation. Another theory involves a disturbance in retinoic acid synthesis by ethanol (5).

Retinoic acid, a vitamin A derivative, has been shown to play an important role in the specification of spatial patterns during the morphogenesis of the nervous system and limbs as well as a role in epithelial cell differentiation. Retinoic acid is considered a morphogen and believed to help establish the anteroposterior axis of both the nervous system and limbs. During ontogeny, retinoic acid probably regulates events that mediate the transcription of genes that control nervous system and limb morphogenesis. This substance appears to be an important developmental signal (5).

An alteration in the synthesis of this molecule may produce adverse effects on the developing organism. Ethanol regulates such a disruption in retinoic acid synthesis and result in teratogenic effects. Ethanol competitively inhibits the alcohol dehydrogenase transformation of retinal or vitamin A into retinal. The conversion of retinol to retinal by this enzyme is believed to be the rate limiting step in the production of retinoic acid. Retinal is then irreversibly oxidized by an aldehyde dehydrogenase to retinoic acid (5).

Retinol dehydrogenase is considered equivalent to class 1 ADH in man. In intoxication states, class 1 ADH is saturated with ethanol. Thus, retinol oxidation is blocked. An investigation suggested that expression of a human class 1 ADH gene is regulated transcriptionally by retinoic acid (5).

Ethanol ingestion may decrease retinoic acid levels and/or its synthesis. Since retinoic acid has been shown to play an crucial role in the specification of special patterns during the morphogenesis of the nervous system and limbs, a reduction in retinoic acid synthesis may well result in birth defects of the central nervous system and limbs (5).

A decrease in the metabolism of retinol by alcohol dehydrogenase may cause an increase in retinol levels and this may be related to the increase in teratogenic effects in offspring of alcoholics. Hypervitaminosis has been associated with birth defects (5).

Ethanol ingestion during pregnancy interferes with retinoic acid synthesis. The relationship between retinoic acid synthesis and alcohol teratogenesis is supported by evidence demonstrating that ethanol competitively inhibits the rate limiting step in the synthesis of retinoic acid, the conversion of retinol to retinal by alcohol dehydrogenase Since a high level of retinoic acid is needed for normal development of the limbs and central nervous system, disruption of its synthesis in these target organs at critical developmental periods would result in defects of these organs (5).

BIBLIOGRAPHY:

Abel, E. and Sokol, R. A Revised Conservative Estimate of the Incidence of FAS and Its Economic Impact. Alcoholism, 0145-6008:514-524 (1991).

Bonthius, D. and West, J. Permanent Neuronal Deficits in Rats Exposed to Alcohol During the Brain Growth Spurt. Teratology, 44:147-163 (1991).

Brodie, C. and Vernadakis, R. Critical Periods to Ethanol Exposure During Early Neuroembryogenesis in the Chick Embryo: Cholinergic Neurons. Developmental Brain Research, 56:223-228 (1990).

Burd, L. and Martsolf, J. Fetal Alcohol Syndrome: Diagnosis and Syndromal Variability. Physiology and Behavior, 46:39-43 (1989).

Keir, W. Inhibition of Retinoic Acid Synthesis and its Implications in Fetal Alcohol Syndrome. Alcoholism. 15/3:560-564 (1991).