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* Department of Human Anatomy and Medical Neurobiology, College of Medicine, The Texas A&M University System Health Science Center, College Station, Texas 77843–1114; and Department of Cell and Developmental Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29208
1To whom requests for reprints should be addressed at Department of Human Anatomy and Medical Neurobiology, College of Medicine, The Texas A&M University System Health Science Center, College Station, TX 77843–1114. E-mail: jrwest{at}medicine.tamhsc.edu
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Key Words: birth defects • brain damage • dysmorphology • fetal alcohol syndrome • teratology
A number of false ideas influenced how teratologists used to interpret the etiology of birth defects and issues related to alcohol teratogenesis. Although early in the 20th century Stockard (1) generated experimental evidence in different animal species that alcohol could be teratogenic, the general belief before the second half of the century was that birth defects were caused by hereditary factors. In 1941, Gregg (2) reported the first convincing evidence of a teratogen by discovering that offspring of pregnant women who contracted German measles early in their pregnancies had congenital malformations. Two decades later, Lenz (3) reported clinical evidence that exposure to the morning-sickness drug thalidomide during the first trimester could cause dramatic limb malformations in offspring. Soon thereafter, teratogens were defined as any environmental agent, viruses, drugs, or possibly any other environmental stimulant that could cause abnormal development. The thalidomide study was a harsh rebuttal to the idea that the placenta was an effective barrier to environmental factors. Unfortunately, the study led to the adoption of another at least partially false idea that although some environmental substances could penetrate the placenta, the embryo was vulnerable during only the first trimester. Although that idea has now been discarded, even recently many in the medical and biological community believe that the conceptus is primarily vulnerable during the first trimester, the major period of organogenesis. We now know, primarily from a large number of detailed fetal alcohol studies, that the developing brain is vulnerable throughout development (4) and the third trimester is an especially vulnerable period for certain teratogens (5).
For both practical and theoretical reasons, teratologists have been slow to identify deficits associated with the central nervous system. Certainly, a main part of the problem is that scientists tend to find what they look for and ignore or overlook what they do not expect to see. Many human and animal studies have shown that the embryo is vulnerable to primary structural malformations during the first trimester. Therefore, later developmental periods have received much less attention. The task of screening pharmaceuticals for teratogenic properties has relied on the most basic evaluation of the brain; basically, if it is present in the embryo and not exposed (exencephalic), it is considered to be normal. Furthermore, because of behavior and of the anatomical complexity of the brain, identifying the etiology for deficits in complex or subtle behaviors has been much more difficult. Morphology may be normal, but this does not necessarily mean that behavior is normal. Environmental agents could act as behavioral teratogens impairing cognitive, social, sensorimotor, or other effective behavior even in the absence of obvious physical problems.
In 1973, the seminal studies by Jones et al. (6) and Jones and Smith (7) identified heavy alcohol exposure as teratogenic. However, many researchers in the 1970s and 1980s were skeptical that alcohol was a teratogen. Today, fetal alcohol syndrome (FAS) is widely recognized. In 1981, the Surgeon General’s warning against drinking alcohol during pregnancy was widely publicized (8), and the Alcoholic Beverage Labeling Act of 1988 required that a specific health warning statement appear on the labels of all containers of alcoholic beverages. In 1996, an Institute of Medicine committee to study FAS recommended that until dose-response relationships are established, pregnant women should avoid drinking throughout pregnancy (9). Nevertheless, some women continue to drink heavily during pregnancy.
Although teratology studies have now been published about alcohol more than any other substance, many compelling questions remain unanswered. Now that we know that alcohol can be teratogenic, what do we do with that information? How much alcohol is dangerous? What is the best approach for reducing or ameliorating the damage from fetal alcohol exposure? How do we identify the women at greatest risk for abusing alcohol during pregnancy and convince them to reduce their drinking? Why do some women who drink heavily during pregnancy have babies with full-blown FAS whereas other women who reported drinking similar amounts have babies who are much less affected? What are the risk factors associated with damage? Will identifying the mechanisms of damage provide the rationale for effective intervention strategies? Is there potential for therapeutic intervention for children already damaged by gestational alcohol exposure?
The purpose of this symposium was to provide a current assessment of FAS. The focus on FAS was important not only because it represents the most common known cause of mental retardation in the Western world, but also because it occupies a key role in the teratology field. The symposium was timely in at least two ways. First, it summarized the state-of-the-art work in the field. Second, it served as an example to emphasize an effective approach to studying environmentally induced birth defects, particularly those related to the central nervous system. Research on FAS represents one of the most comprehensive bodies of work in the teratology field.
This symposium, entitled "Fetal Alcohol Syndrome," was presented as a symposium at the Association of Anatomy, Cell Biology and Neurobiology Chairpersons Annual Meeting in Maui, Hawaii, on January 21, 2005. The Society for Experimental Biology and Medicine is grateful to James R. West, Ph.D., and Charles A. Blake, Ph.D., for organizing the meeting and to James R. West, Ph.D., for organizing the symposium. There were five speakers, followed by a discussion period.
Edward P. Riley, Ph.D., presented an overview of the human structural and functional deficits resulting from fetal alcohol exposure and emphasized its economic ramifications. Dr. Riley discussed the range of deficits that are grouped into a broader category called fetal alcohol spectrum disorders (FASD). He focused on changes in brain structure and a variety of neuropsychological and motor impairments observed in children.
Kathleen K. Sulik, Ph.D., described the similar facial features of children with FAS and those of mice exposed to alcohol during early development. Dr. Sulik also compared the facial malformations of other causes, such as DiGeorge syndrome. Focusing on ethanol-induced alterations in gene expression and cell death of neural crest cells, she considered putative mechanisms of damage and the initial attempts to diminish alcohol-induced dysmorphogenesis.
Joanne Weinberg, Ph.D., focused on the complicated areas of fetal alcohol exposure and the resulting alterations in neuroendocrine regulation and immune function. Dr. Weinberg demonstrated how fetal programming with an environmental teratogen could increase the vulnerability to illness or other disorders that have long-term consequences.
Timothy A. Cudd, D.V.M., Ph.D., focused on the use of animal research in the fetal alcohol field. Dr. Cudd pointed out that we have championed the use of animal model systems to answer questions that, for ethical and practical reasons, cannot be addressed easily in humans. He evaluated several different species on their advantages and disadvantages and the types of questions for which they might be best used for fetal alcohol research.
Charles R. Goodlett, Ph.D., focused on the cellular and molecular mechanisms underlying fetal alcohol damage. In spite of increased awareness of the adverse effects of drinking during pregnancy, the incidence of FASD has not been reduced. Therefore, Dr. Goodlett presented novel approaches directed toward the prevention and ameliorating consequences of heavy maternal drinking on offspring development.
Some of the speakers have been joined by colleagues to author the following set of up-to-date overviews of the topics they presented at the symposium. In addition, the edited recorded comments from a discussion led by Feng C. Zhou, Ph.D., that followed the last presentation are included. The comments of the audience and speakers added an interesting dimension to the symposium.
As a consequence of the symposium, we now have a better understanding of teratology in general and FAS in particular. Today, animal and human studies are driving each other. We still do not know all the answers, and some researchers would argue that we still have not formulated all the important questions. Nevertheless, the speakers in this symposium have painted a very clear picture of where the FAS field has been, where it is now, and where we should be moving in the future. It is hoped that this symposium and its publication will stimulate cross-disciplinary awareness, interest, and collaboration among biomedical scientists with diverse interests. The models and approaches used in alcohol research may generate important data and provide insight to scientists’ research and foster communication and collaboration among scientists in different fields.
Support for the symposium was generously provided by the National Institute for Alcohol Abuse and Alcoholism.
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