Long-Chain Alcohol Found To Block Mechanism of Fetal Alcohol Syndrome

An article in todays Federation of American Societies for Experimental Biology (FASEB) Journal (Chen, S; Wilkemeyer, M; Sulik, K; and Charness, M. Octanol antagonism of ethanol teratogenesis, FASEB J. 10.1096/fj00-08620fje and Volume 15, Number 9, July 2001) reports that the long-chain alcohol 1-octanol successfully blocks a mechanism leading to fetal alcohol syndrome (FAS). Viewed as paradoxical because it is the short-chain alcohol ethanol (beverage alcohol) that causes FAS, todays finding nevertheless suggests a strategy for developing pharmaceutical interventions to prevent alcohol-related birth defects.

"For more than 20 years, alcohol researchers have been working to unravel the mechanisms of fetal alcohol damage in order eventually to develop potent interventions. Todays report of a compound that can block fetal alcohol damage in mouse whole embryos suggests that the fetus is amenable to treatment," said Enoch Gordis, M.D., Director, National Institute on Alcohol Abuse and Alcoholism. The study was supported by the NIAAA and the Department of Veterans Affairs and conducted by Shao-Yu Chen, Ph.D., and Kathleen K. Sulik, Ph.D., of the University of North Carolina School of Medicine and Michael E. Charness, M.D., and Michael F. Wilkemeyer, Ph.D., of Harvard Medical School.

The leading preventable cause of mental retardation, FAS exacts a heavy toll on U.S. society. In addition to human costs, FAS imposes lifetime economic costs estimated at $1.8 million per child in health care and indirect costs such as lost productivity. An estimated 3 to 30 infants per 10,000 live U.S. births and about 6 percent of the offspring of alcoholic mothers are diagnosable with FAS.

NIAAA supports research into multiple mechanisms whereby alcohol is believed to damage the developing fetus. Previous work by Drs. Wilkemeyer, Charness, and colleagues showed that ethanol inhibits cell adhesion mediated by the L1 cell adhesion molecule in selected host cells (Alcohol inhibits cell-cell adhesion mediated by human L1. The Journal of Cell Biology 133(2):381-390; see News Release, April 15, 1996 at www.niaaa.nih.gov) and that low concentrations of 1-octanol can antagonize that effect (Antagonists of alcohol inhibition of cell adhesion. Proceedings of the National Academy of Sciences 97:3690-3695; see News Release, March 21, 2000 at www.niaaa.nih.gov). Todays study advances the work to mouse whole embryo cultures and demonstrates that 1-octanol can block alcohol teratogenesis (abnormal physical development) and associated excessive apoptosis (programmed cell death).

For todays study, the researchers cultured 23 mouse embryos with ethanol and 23 embryos with both ethanol and octanol. Eighteen control embryos were exposed to neither ethanol nor octanol. The results were dramatic: Control embryos and embryos exposed to both ethanol and octanol were developmentally more advanced and exhibited less cell death than embryos cultured with ethanol alone.

"Our findings suggest that ethanol disruption of L1-mediated cell adhesion contributes to its teratogenic actions through the induction of cell death. This suggests an avenue for the development of safe compounds for the prevention of FAS," said Dr. Charness, Associate Professor in the Department of Neurology, Harvard Medical School, and Chief of Neurology, VA Boston Healthcare System. "It is quite possible that compounds related to octanol may also prove useful in antagonizing a variety of ethanol effects."

Scientists have long known that drinking leads to adverse health effects on the developing fetus. When a woman drinks alcohol during pregnancy, her fetus is at risk of spontaneous abortion, FAS, and other birth defects. Children with FAS exhibit brain damage, growth retardation, and a characteristic pattern of facial malformations, whereas those with less severe alcohol-related birth defects (ARBD) exhibit neurobehavioral deficits.

"Our research indicates that many of the devastating effects of maternal alcohol abuse probably occur during the first 3-6 weeks of pregnancy. At this time, most women do not yet know they are pregnant," said Dr. Kathleen Sulik, a professor at University of North Carolina Medical School, Chapel Hill, and the director of the Fetal Toxicology Division, Bowles Center for Alcohol Studies. According to a survey conducted by the Centers for Disease Control, 45 percent of women consume alcohol during the 3 months prior to learning that they are pregnant and 5 percent consume at least 6 drinks per week.

"We still do not know if there is a safe dose of alcohol that can be consumed by pregnant women," stated Dr. Gordis in a recent issue of NIAAAs Alcohol Alert bulletin (Number 50, December 2000). "The only responsible advice to women who wish to become pregnant and those who are pregnant is to avoid alcohol use entirely. Unfortunately, many women continue to drink during pregnancy . . . and many of the women who continue to drink are at highest risk for having children with fetal alcohol syndrome and related problems. Finding potent ways to reach populations at risk . . . remains a challenge for alcohol research."

The full article text and accompanying figures may be viewed at www.fasebj.org after 12:01 A.M. May 18, 2001.

For interviews with Dr. Charness, telephone 617/325-2815 or e-mail mcharness@hms.harvard.edu. For interviews with Dr. Sulik, telephone 919/966-3208. For interviews with Dr. Gordis, telephone NIAAA Press, 301/443-0595. Additional alcohol research information and publications are available at www.niaaa.nih.gov.

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.