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For years, physicians and scientists have known that alcohol has detrimental effects on the human fetus. A new study from investigators in Berlin, Tokyo and St. Louis suggests how the damage associated with fetal alcohol syndrome might occur.
A paper in the Feb. 11 issue of Science reports that a single exposure to high levels of ethanol (the alcohol in beer, wine and spirits) can kill nerve cells in the developing brain. The researchers found that the rat brain is sensitive to this toxic effect during a brain development stage that corresponds to the brain growth spurt in humans. The brain growth spurt lasts from about the sixth month of pregnancy to a child's second birthday.
The scientists intoxicated infant rats by giving them ethanol for periods of four or more hours. This maintained the alcohol level at about twice the level that defines legal intoxication in humans. This one-time exposure caused brain cells to commit suicide by a process called apoptosis or programmed cell death. The rate of cell death exceeded the spontaneous rate of cell death by almost 30 times in some parts of the brain (spontaneous cell death removes surplus cells from the developing brain).
"For many years, scientists studying fetal alcohol syndrome have tended to expose rats to alcohol for longer periods of time rather than studying the damage more transient exposure might cause," said John W. Olney, M.D., the study's senior investigator and the John P. Feighner Professor of Neuropsychopharmacology at the School of Medicine. "We exposed the infant rats just once, keeping them intoxicated for a period of just a few hours, and we found that was sufficient to trigger considerable damage."
The paper's lead author, Chrysanthy Ikonomidou, M.D., associate professor of pediatric neurology at Humboldt University in Berlin, previously was a postdoctoral fellow in Olney's laboratory, as was another author, Masahiko J. Ishimaru, M.D., Ph.D., now based at the Tokyo Medical and Dental University.
The researchers found no evidence that exposure to small amounts of alcohol had cumulative effects on the developing brain. Rather, substantial intoxication was required before significant damage occurred. While translating effects from rats to humans is difficult, Olney believes it is unlikely that a single glass of wine would cause the damage observed in these experiments, even if expectant mothers consumed a very small amount of alcohol every day. Because it is not entirely clear how rats and humans compare in sensitivity to alcohol, however, the investigators believe it is best to avoid alcoholic drinks completely during pregnancy.
The investigators also studied the mechanism of this alcohol-induced brain cell death. It is known that alcohol can interfere with certain transmitter systems in the brain. The systems use chemical molecules, such as glutamate and GABA, to activate nerve cell receptors and transmit messages from one cell to another. In research reported last year in Science, Olney and colleagues found that drugs called NMDA antagonists, which interfere with glutamate transmission in the same way that alcohol does, have a similar cell-killing effect in the infant rat brain when given as a single high dose. In the current study, the investigators found that drugs that excessively activate GABA receptors, as alcohol does, also can kill nerve cells in the infant rat brain.
"Our evidence documents that alcohol acts by two mechanisms -- blockade of glutamate transmission and excessive stimulation of GABA transmission. By combining these two mechanisms, it produces a compound pattern of damage that is greater than either mechanism would produce by itself," Olney said.
The death of neurons by apoptosis occurs naturally. It enables the brain to get rid of unhealthy cells or cells that are not needed for normal brain development. "But what we saw was cell death at many times the normal rate," Ikonomidou said. "And alcohol and these other drugs don't just cause cells that are going to die anyway to die more quickly. They cause cells that never would have died under normal circumstances to commit suicide -- and millions are involved."
These mechanisms might contribute to the wide variety of neurological and psychiatric symptoms seen in individuals with fetal alcohol syndrome. Symptoms range from hyperactivity and learning disabilities in childhood to depression or severe psychosis in adulthood. Olney believes the variety of symptoms could be explained by the timing of alcohol exposure. In rats, he found that different populations of neurons were vulnerable at different times during the brain growth spurt.
