Sobering Work.

Unraveling alcohol's effects on the developing brain

At parties, young women often want to talk to James R. West. Sure, he's a charming guy, but they especially want to talk about his work--and how it may touch them personally. The issue is potentially close at hand: West studies the effects of alcohol on a baby's developing brain.

"People always ask me, How much is too much?" says West, a neurobiologist at the Texas A&M University Health Science Center in College Station. "We don't really know."

A decade ago, scientists thought there would be a straightforward answer. But recent findings indicate that alcohol doesn't have a single threshold as it acts on different biochemical pathways and different parts of the brain. So, it isn't clear when and where in human fetuses the trouble starts.

Fetal alcohol syndrome was first described in France in the late 1960s and in the United States a few years later. The condition was difficult to recognize because not every woman who drinks heavily during pregnancy bears a baby with the characteristic physical and behavioral abnormalities.

Today, out of each 10,000 children born in the United States, between 3 and 30 suffer from fetal alcohol syndrome. These babies are small at birth, with distinctive facial features, including a flattened area between the nose and upper lip, narrow upper lips, small eyes and noses, and narrow foreheads.

Their mother's drinking has affected their central nervous system as well: Fetal alcohol syndrome is the leading cause of nonhereditary mental retardation.

Children with the outward signs of the syndrome may represent only the most severe example of a spectrum of detrimental effects. Alcohol-exposed children who lack the characteristic facial features of fetal alcohol syndrome may still suffer from attention problems, hyperactivity, aggression, and psychiatric illnesses. Some youngsters may have trouble functioning independently, though they have normal intelligence as measured by IQ tests.

Many recent studies indicate that alcohol doesn't uniformly interfere with the function of every cell in a fetal brain. Sensitive imaging techniques have revealed that alcohol damages some parts of the developing human brain more than others.

Moreover, it targets particular biochemical pathways vital to the development, function, migration, and survival of certain nerve cells, says Kenneth Warren of the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Md. No single mechanism is likely to account for all of the structural, functional, and behavioral problems that have been attributed to prenatal alcohol exposure, he says.

The ultimate goal of research in this area is to identify new ways of blocking or mediating some of alcohol's harmful effects, says Warren. Better knowledge of underlying mechanisms may help researchers figure out how to rescue cells or predict which infants are most at risk from alcohol exposure, he says.

When researchers started looking at the brains of youngsters with fetal alcohol syndrome, the damage seemed so pervasive that the investigators assumed alcohol must affect every system in the developing brain. For example, alcohol might disrupt cell function by altering the integrity of the membranes. Alternatively, alcohol might damage or kill cells indiscriminately by increasing the production of free radicals, toxic byproducts of oxygen metabolism.

"One of the major changes in the alcohol field in the last 10 years has been the identification of proteins that alcohol might interact with directly," says Michael E. Charness of Harvard Medical School in Boston. For example, researchers have identified specific effects on molecules that regulate development and others that participate in cell signaling.

The cell-adhesion molecule called L1 guides cell migration in the developing brain. This protein regulates nerve-cell adhesion and movement, processes critical to getting the cells to their proper position in a developing brain. Charness and his colleagues gave specific nerve cells growing in laboratory cultures alcohol concentrations equivalent to those resulting when a woman has one to two drinks. This alcohol can prevent nerve cells guided by L1 from adhering to each other, Charness says.

In a pregnant woman, this effect may interfere with the fetus's developmental steps, he says. Whether these changes would be significant enough to disrupt brain function in people or animals, however, is still unknown.

Ethanol is the alcohol in beer, wine, and other drinks. In experiments reported in the March 28 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Charness and his colleagues found that some other forms of alcohol, such as octanol, can block ethanol's action. Their results suggest that ethanol targets a specific area on L1, Charness says.

Besides encouraging cell adhesion, L1 can trigger nerve cells to grow toward each other and form connections. Ethanol concentrations mimicking a woman's exposure to a single glass of wine seem to slow the growth of such connections, reports Cynthia F. Bearer of Case Western Reserve University School of Medicine in Cleveland.

Other researchers have found that genetic mutations in L1 result in damage to the corpus callosum, the bundle of fibers that connects the brain's two sides, Charness says. Interestingly, this part of the brain is often abnormal in children with fetal alcohol syndrome.

In the past few years, researchers have also explored alcohol's effects on molecules that play a role in nerve signaling. One recent study has shown that high concentrations of alcohol--the equivalent of about twice the legal limit for driving in most states--block cells' receptors for a chemical known as glutamate, which stimulates nerve-cell signaling. The study at Washington University School of Medicine in St. Louis also found that alcohol activates receptors for gamma-aminobutyric acid, better known as GABA, which inhibits signaling.

Work by other scientists indicates that ethanol may interfere with serotonin, another important chemical in nerve signaling.

When they don't receive enough input from other cells, "neurons get the message they are not developing normally," says John W. Olney of Washington University. "This activates a program that says, `You will not reach your biological destiny, so kill yourself.'"

In young rats going through a brain growth spurt equivalent to that of a third-trimester human fetus, a single episode of intoxication lasting about 4 hours is enough to kill off groups of nerve cells, Olney and his colleagues reported in the Feb. 11 SCIENCE. By changing the time at which the animals are exposed to alcohol and thus when their normal nerve signaling is disrupted, the researchers can trigger nerve-cell loss from many different regions of the brain, says lead researcher Chrysanthy Ikonomidou of Humboldt University in Berlin.

His team found no evidence that exposure to low concentrations of alcohol, even for a longer period of time, cause damage to a fetus. Therefore, Olney says, "one glass of wine with dinner is not likely to be harmful. But beyond that, it is anyone's guess because there is no way we can extrapolate from rats to man with any precision."

Since 1991, the proportion of pregnant women drinking, on average, the equivalent of at least a glass of wine a day has quadrupled, according to the federal Centers for Disease Control and Prevention. Today, 1 in 29 women carrying unborn babies report such drinking, which CDC calls "risky." About half of these women also reported binge drinking, or downing the equivalent of more than five glasses of wine on any one occasion.

Because researchers haven't been able to establish a safe amount of alcohol for given periods of pregnancy, public health messages tell women to avoid drinking any alcoholic beverages during their pregnancies.

Many animal studies find no harmful effects on fetuses from exposures to less alcohol, adjusted for body size, than the amount needed to give a person a buzz. Although it's impossible to say with certainty that fetal development in any two species will have identical sensitivity to alcohol, some scientists contend that probably only high doses of alcohol damage a fetus.

Research on the effects of alcohol on brain cells supports the idea that more alcohol is worse than less alcohol, West says. He adds that drinking any amount of alcohol relatively quickly is probably more dangerous than drinking an equal amount over a longer period of time.

Right now, there's no "morning-after pill" to give to pregnant women who drink or any other method of curing the damage caused by exposure to alcohol during a critical period of fetal development, says Boris Tabakoff of the University of Colorado Health Sciences Center in Denver. "If you wait 'til a woman drinks, and she drinks during [a] critical period, there may be no way to intervene."

The current research on alcohol may eventually translate into treatments for some of those women, Tabakoff says. It's unlikely, however, that all of alcohol's effects on the developing brain could be blocked, he adds.

Charness' work shows that it's possible to use other alcohols to deter ethanol's effects on L1-driven cell adhesion--at least in the test tube. Such findings "may lead eventually to medications that reduce the damaging effects of alcohol in both fetal development and in adults," Charness speculates.

However, Ikonomidou says that her findings--that nerve cells may die within hours after exposure to a single high dose of alcohol--convince her that no treatment will be effective in compensating for alcohol's effects.

One of the dilemmas facing researchers and physicians alike is that it can be difficult to identify both mothers-to-be who're drinking and their affected kids, says Bearer. This problem is especially difficult because some kids with neurologic damage don't have the characteristic facial features of fetal alcohol syndrome.

In the March 1999 ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH, Bearer and her colleagues reported that alcohol metabolites in meconium--the first stool of a newborn--can distinguish between women who drank alcohol late in pregnancy and those who didn't.

Bearer is now trying to see whether such biochemical clues can identify how much alcohol a fetus was exposed to and when. That knowledge may indicate which brain areas were likely to have been damaged, she speculates.

Several researchers are trying to create maps of the areas damaged after fetal animals are exposed to alcohol at certain times, says Kathleen K. Sulik of the University of North Carolina at Chapel Hill. These maps might be useful in pinpointing when during pregnancy, alcohol is most likely to be harmful, says Sulik.

Detailed magnetic resonance images of kids with and without fetal alcohol syndrome have shown that some brain structures are more likely than others to be damaged by alcohol, says Edward P. Riley of San Diego State University. His team finds the frontal cortex and corpus collosum to be especially vulnerable, a result that fits well with Charness' work on L1.

Now, Riley's group is working to correlate the observed brain changes with behavioral and cognitive effects seen in children exposed to alcohol in the womb. Riley says that the preliminary evidence supports such links.

All the researchers agree that there's no easy answer to the question that West often faces, Can a woman drink some limited amount of alcohol without threatening normal fetal development?

"If the agent was, say, something in bathroom cleaner, people would just stay away from it," West says. "However, since it is alcohol, and they don't want to give it up, they are interested in how much they can `get away with.'"

The scientists vary somewhat in their responses. Charness says, "Biochemical studies suggest there is potential for harm at low doses of alcohol."

West offers, "It's unlikely that a drink once in a while is going to cause any damage, but we don't know for sure."

Sulik adds, "I happen to believe that it takes a high blood-alcohol concentration to cause problems [for the fetus], but the bottom line is that we don't know, and better safe than sorry."

Determining the smallest amount of alcohol that would harm a fetus would require knowing which developmental steps and which underlying mechanisms may be disrupted by alcohol, Riley says. Even if that information became clear in animal studies, translating the findings into practical advice might prove difficult. Species differ in developmental patterns, and many women don't know exactly when they became pregnant.

The consensus of these basic scientists, then, is that the only safe drink for a pregnant woman is one without alcohol. After all, Riley says, "how many cigarettes cause cancer?" Just one cigarette--or one drink--may be unlikely to cause problems, he notes, but so far, the possibility that it does some harm can't be ruled out.