Academic journal article Alcohol Research

Mechanism of Alcohol-Induced Damage to the Developing Nervous System

Academic journal article Alcohol Research

Mechanism of Alcohol-Induced Damage to the Developing Nervous System

Article excerpt

Numerous mechanisms likely contribute to the damaging effects of prenatal alcohol exposure on the developing fetus and particularly the developing central nervous system (CNS). The coexistence of a multitude of mechanisms that may act simultaneously or consecutively and differ among various cell types poses particular challenges to researchers. To study alcohol's effects on the fetus more easily, investigators have used animal models and tissue-culture experiments. Such approaches have identified numerous potential mechanisms through which alcohol acts on the fetus, many of which result in cell death by necrosis or apoptosis. Among these mechanisms are increased oxidative stress, damage to the mitochondria, interference with the activity of growth factors, effects on glia cells, impaired development and function of chemical messenger systems involved in neuronal communication, changes in the transport and uptake of the sugar glucose, effects on cell adhesion, and changes in the regulation of gene activity dur ing development.

KEY WORDS: prenatal alcohol exposure; central nervous system; oxidative stress; mitochondria; growth-arresting factors; embryologic development; alcohol-related intrauterine disorder; alcohol-related neurodevelopmental disorder; necrosis; neurotransmitters; glucose intolerance; cell adhesion molecules

Maternal drinking during pregnancy can adversely affect the outcome of the off offspring, with effects ranging from mild cognitive impairment, characterized by impaired mental activities, to full-blown fetal alcohol syndrome (FAS), characterized by growth deficiency, central nervous system (CNS) disorders, and a pattern of distinct facial features. Alcohol can exert these effects both directly, by acting on fetal tissue, and indirectly, by interfering with the maternal support of the growing fetus. Such indirect mechanisms include altering the placenta's ability to provide the necessary nutrients to the developing fetus. Alcohol also may indirectly harm the fetus by impairing the mother's physiology. For example, alcoholism may lead to malnutrition or be combined with other drug use.

This article concentrates on the mechanisms underlying alcohol's direct effects on the fetus. Numerous mechanisms have been suggested as contributing to alcohol-induced fetal damage, particularly deficits in brain function, although none of these mechanisms has been established with certainty. Furthermore, although alcohol itself generally is considered the primary birth-defect-inducing substance (i.e., teratogen), products resulting from alcohol's breakdown (i.e., metabolism) also may play a role. For example, acetaldehyde--a toxic chemical formed by the breakdown of alcohol in the liver and other tissues--can accumulate in the feral brain after prenatal alcohol exposure (Hamby-Mason et al. 1997) and may contribute to the development of FAS. Recent literature reviews confirm that no single putative mechanism can account for all the components and variations of the anatomical and behavioral characteristics (i.e., phenotypes) found in children prenatally exposed to alcohol (Abel and Hannigan 1995; Guerri 1998; Maier et al. 1996; Michaelis 1990; Michaelis and Michaelis 1994; Phillips et al. 1989; Schenker et al. 1990; West et al. 1994).

This article reviews some general challenges researchers face when trying to elucidate multiple disease mechanisms and explains the role that animal and tissue culture (i.e., in vitro) studies can play in this research. The article then explores some of the mechanisms that have been implicated in the development of alcohol-induced CNS deficits, which represent the most serious consequences of prenatal alcohol exposure.

CHALLENGES ASSOCIATED WITH THE PRESENCE OF MULTIPLE MECHANISMS

Identifying the mechanisms contributing to alcohol-induced fetal damage is complicated by numerous factors. For example, scientists have not determined the exact cellular and molecular processes involved in normal CNS development, making it difficult to tease apart the effect that alcohol has on this system. …

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