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Researchers Identify Damage Mechanism in
Fetal Alcohol Syndrome
St. Louis, Feb. 11, 2000
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 identifies how
the damage associated with fetal alcohol syndrome might occur.
A paper in todays 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. Called synaptogenesis
because it is the time when brain cells form most of their
interconnections, the brain growth spurt lasts from about
the sixth month of pregnancy to a childs second birthday.
In rats, synaptogenesis occurs after a pup is born.
The scientists intoxicated infant rats by giving them ethanol
for periods of four or more hours. This maintained the alcohol
level at about 0.2 (200 mg ethanol per deciliter of blood)
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
The investigators say finding that cells can die after
a single episode of alcohol intoxication means it would be
prudent for expectant mothers to avoid alcohol intoxication
"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 studys
senior investigator and the John P. Feighner Professor of
Neuropsychopharmacology at Washington University School of
Medicine in St. Louis. "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 in the developing brain."
The papers lead author, Chrysanthy Ikonomidou, M.D.,
associate professor of pediatric neurology at Humboldt University
in Berlin, previously was a postdoctoral fellow in Olneys
laboratory, as was another author, Masahiko J. Ishimaru, M.D.,
Ph.D., who now is based at the Tokyo Medical and Dental University.
The three collaborated with other colleagues at their institutions
to conduct the study. 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.
Much of the significance of the findings comes from the fact
that alcohol is so widely used throughout the world. "However,
it must be recognized that numerous other drugs act either
by blocking glutamate receptors or activating GABA receptors,
and many of these drugs are drugs of abuse and/or are used
in pediatric medicine as sedatives, anticonvulsants or anesthetics,"
Olney said. "In fact, the only drugs available for anesthetizing
human infants act either by blocking NMDA receptors or activating
Drugs of abuse that block NMDA glutamate receptors include
phencyclidine (PCP or "angel dust"), ketamine (special
"K") and nitrous oxide (laughing gas). Both ketamine
and nitrous oxide are used frequently in pediatric anesthesia.
GABA receptor activators that are frequently abused and/or
used in pediatric anesthesia include benzodiazepines, barbiturates,
isoflurane and propofol.
"In light of this new evidence, it obviously is prudent
for expectant mothers to avoid any of these drugs," Olney
said. "It also will be important to carefully reevaluate
how these drugs are used in pediatric medicine with an aim
toward developing guidelines that ensure an adequate margin
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 explained. "And alcohol and these other drugs
dont 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
These mechanisms may 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 may be explained by
the timing of alcohol exposure. In the rat, he found that
different populations of neurons were vulnerable at different
times during synaptogenesis.
"So if the toxic event occurs early in synaptogenesis,
it will delete groups of neurons that develop sensitivity
early. If it occurs later, those neurons will be spared, but
other groups will be deleted," Olney explained.
Olney and Ikonomidou will continue to investigate the impact
of alcohol and drug exposure on the developing brain by studying
rats as the animals mature. They will determine which specific
brain damage patterns are associated with specific behavioral
and neurological problems that develop later in life.
"Many psychiatric and neurological disorders are thought
to originate from events that occur during development,"
Olney explained. "This model will allow us to establish
some correlations between damage to specific cell populations
during development and subsequent neuropsychiatric problems."
This research was supported by grants from the National Institute
of Mental Health, the National Institute on Aging, the National
Institute on Drug Abuse, the National Eye Institute, the National
Alliance for Research on Schizophrenia and Depression, the
Deutsche Forschungsgemeinschaft (DFG) and Humboldt University.
C. Ikonomidou, et al. Ethanol-Induced Apoptotic Neurodegeneration
and the Fetal Alcohol Syndrome. Science, vol. 287 p1056-1060,
Feb. 11, 2000.
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