Modeling Alcohol's Effects on Organs in Animal Models

Alcohol Research & Health,  Spring, 2000  by Biddanda C. Ponnappa,  Emanuel Rubin

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Researchers have developed numerous animal models to investigate the development of various alcohol-related diseases. Such models have provided insights into the mechanism through which alcohol can induce liver damage. Animal models also have helped researchers explore the mechanisms by which both short-term (e.g., binge) and long-term drinking can interfere with the function of the heart, a condition referred to as alcoholic cardiomyopathy. Furthermore, animal models have provided substantial information on the causes of fetal alcohol syndrome. Such models have demonstrated that exposure to alcohol during gestation can lead to prenatal and postnatal growth retardation, characteristic facial malformations, immune system deficiencies, and alterations in the central nervous system.

KEY WORDS: animal model; chronic AODE (effects of AOD [alcohol or other drug] use, abuse, and dependence); in vitro study; body part; body fluid; alcoholic liver disorder; alcoholic cardiomyopathy; fetal alcohol syndrome; alcohol-related neurodevelopment disorder; ethanol metabolism

Long-term (i.e., chronic) alcohol use affects almost every organ system of the body, potentially resulting in serious illnesses, including liver disease, impaired heart function (i.e., cardiomyopathy [1]), and inflammation of the pancreas (i.e., pancreatitis). Even one-time (i.e., acute) alcohol consumption, such as binge drinking, can temporarily alter the activity of many organ systems. Furthermore, heavy alcohol consumption by a pregnant woman can harm her fetus and lead to fetal abnormalities ranging from mild learning deficits to full-blown fetal alcohol syndrome (FAS). Investigating the mechanisms underlying these adverse effects of alcohol consumption in humans frequently is impractical, because alcohol-related disease generally develops only after many years of heavy drinking. Other studies would be unethical to conduct in humans. Therefore, researchers have been forced to use various animal models to gain insight into the processes responsible for alcohol's effects on the body and to determine new wa ys of preventing or treating alcohol-related diseases.

This article reviews numerous animal models used to explore alcohol's effects on several organ systems. First, it provides a brief overview of the animal species and modes of alcohol administration used in such studies. The, article then summarizes the results of studies aimed at identifying the mechanisms underlying alcohol-induced liver damage, alcoholic cardiomyopathy, and FAS.

APPROACHES TO STUDYING ALCOHOL's EFFECTS ON ORGAN SYSTEMS

Animal Species

To model alcohol's effects on the human body, researchers ideally wish to use animals closely related to humans, such as nonhuman primates. However, practical and economic considerations generally preclude the use of these animals. In one instance in which primates were used as a model system, however, researchers studied baboons that consumed alcohol with their diets for several years. One-third of these animals eventually developed cirrhosis of the liver (Rubin and Lieber 1974), conclusively demonstrating alcohol's liver toxicity independent of nutritional factors. To date, however, this experiment represents the only instance in which experimental alcohol administration induced cirrhosis in an animal model. Furthermore, the experiment lasted several years and led to disease development in only a minority of the animals studied. Consequently, the utility of this model for studying the pathogenesis of alcohol-related diseases is limited.

Researchers have used numerous other animals to test alcohol's effects, most commonly mammals, such as rats, mice, rabbits, hamsters, ferrets, and dogs. Some behavioral and genetic studies have also been conducted in the fruit fly Drosophila melanogaster and in the roundworm Caenorhabditis elegans. Although the choice of the species depends on the nature of the experiment, most studies have been conducted in rats, owing to their manageable size, ease of handling, low cost, and the availability of extensive scientific data.

In Vitro Approaches. Many studies have been conducted in vitro--that is, nor with intact animals but with isolated organs, tissues, or cells. For example, researchers have used isolated, perfused organs; tissue slices; suspensions of individual cells; cultures of cells newly isolated from an organism (i.e., primary cell cultures); cells that have gained the ability to grow indefinitely (i.e., transformed cell lines); and isolated cell structures (i.e., organelles).

To study alcohol's effects on an organ (e.g., the liver or heart), researchers sometimes isolate the particular organ and keep it functional by perfusing it-- that is, by passing a fluid or medium through it. Under these conditions, all the different cell types within that organ continue to function in their normal relationships with each other. This is particularly important in organs that comprise several cell types, such as the liver, which contains hepatocytes, endothelial cells, Kupffer cells, stellate cells, and bile duct epithelium, each of which has a specialized role in keeping the liver functioning. By perfusing such organs with fluids containing various alcohol concentrations, researchers can study the coordinated response of all cell types to alcohol. At the same time, the influence of additional factors that might affect organ function in the intact organism (e.g., hormones) is eliminated in the perfused organ. A potential limitation of this approach is that such perfusion experiments last only a few hours before the organ fails.