Gestational exposure to ethanol in humans has been shown to cause numerous defects, and the brain is one of the most sensitive targets. These defects are widely diverse, extremely severe, and depend greatly on the dose and timing of ethanol exposure. In fact, recent reviews of the literature indicate that multiple mechanisms (all of which have not been fully elucidated) mediate the adverse outcomes of children prenatally exposed to ethanol. An extensive review of this literature is beyond the scope of this article, so we present highlights of the key neural effects of developmental ethanol exposure. The main postulated causative mechanisms for ethanol-induced brain alterations are as follows (reviewed in: Costa and Guizzetti 1999; Goodlett and Horn 2001; Guerri 1998):
2. Alterations in GABA, NMDA, serotonin, muscarinic cholinergic neurotransmitters systems, and potentially other systems, particularly dopamine and neuropeptide Y
3. Interferes with growth factor functions, resulting in alterations to the proliferation of neuronal precursor, impairing their migration and inducing premature apoptosis
4. Effects on astrocyte formation resulting in misguidance of neuron growth
6. Alteration of cell adhesion molecule function, particularly L1, which results in interference with the cell clustering needed for appropriate brain development
Neonatal treatment of rats during rapid brain growth (third trimester human equivalent), with ethanol, which acts as both a GABA agonist and a NMDA antagonist, causes extensive neurodegeneration. Prenatal exposure, even in modest amounts, has been shown to decrease the number and function of NMDA receptors (Olney et al. 2001). GABA- and NMDA-induced defects may play a role in the mental and behavioral abnormalities seen in alcohol-exposed human offspring, especially since GABA is a trophic factor in the development of other neurotransmitter systems (Lauder et al. 1998). Ethanol-induced serotonergic changes have also been seen in mice and rats treated with ethanol in liquid diets for the majority of the gestational period (Zhou et al. 2001). This form of exposure can have overwhelming effects, since serotonin neurons innervate and communicate with almost the entire population of neurons in the brain. Three types of changes are seen in serotonergic neurons in ethanol-exposed offspring, altered movement of their final location, changes in their nerve fiber growth, and neuron loss. Fewer signals from these serotonergic fibers can result in inappropriate formation of the cortical brain region. The brain muscarinic cholinergic neurotransmitter system can also be affected by exposure to ethanol during development. In fact, it has been shown that exposure of rats to ethanol from PN 4 to 10 (rapid brain growth period) causes the inhibition of muscarinic receptor-stimulated phosphoinositide (PI) metabolism (Balduni and Costa 1989). This effect was seen after a neonatal exposure but not after an adult exposure. It has been postulated that the molecular target for the action of ethanol on the muscarinic-receptor second messenger system is G-protein coupling. As outlined above, developmental exposure to ethanol can also alter the normal growth and migration of neuronal cells. This outcome can result from several ethanol-induced neural alterations. One mechanism by which this occurs was demonstrated by Miller and Robertson (1993), who observed that a prenatal exposure to ethanol caused premature differentiation of radial (guiding) glia cells into astrocytes, resulting in abnormal positioning of cerebral cortex neurons. In addition, ethanol exposure during development has been shown to alter neu-rotrophic factors and the adhesion molecule L1.
Immune deficits have also been seen after gestational exposure to ethanol. Human and animal studies have frequently demonstrated a decrease in T cell number (Ewald and Walden 1988; Ewald 1989) and function (Basham et al.1998; Chang et al. 1994; Gottesfeld and Ullrich 1995; Monjan and Mandell 1980; Norman et al. 1989; Redei et al. 1989; Seelig et al. 1996; Tewari et al. 1992; Weinberg and Jerrells 1991) with gestational or neonatal exposures of varying length. The majority of these studies delivered ethanol in a chronic dosage as a component of a liquid diet or in the drinking water. This chronic-exposure regimen produced more consistent immune deficits than have binge-drinking models (Basham et al. 1998). However, just how these immune alterations are related to the produced neural defects is unclear. One potential mechanism whereby the extensive CNS changes might affect offspring immune function is via the second messenger alterations to the muscarinic cholin-ergic system. Alternatively, it is also known that gestational and neonatal exposure to ethanol which cause immune deficits in offspring (review in: Chiappelli and Taylor 1995; Gottesfeld and Abel 1991; Jerrells 1991; Johnson et al. 1981) also cause changes in the sympathetic nervous system in immune organs (Basta et al. 2000; Gottesfeld et al. 1990). The immune changes might also be initiated by changes to the GABA, NMDA, or serotonin neurotransmitters in the brain due to additional downstream effects. Clearly, additional studies are necessary to determine which, if any, of the ethanol-induced nervous system deficits influence or induce the immune deficits seen after developmental exposure.
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