Alcohol and the human fetal brain

September 13, 2000

In an effort to understand the sensitivity of the human prenatal brain to alcohol, scientists are engaging in a delicate area of research. In a study published in the September issue of Alcoholism: Clinical & Experimental Research, scientists compared the metabolism of alcohol in prenatal human brain and liver tissue with the metabolism in both prenatal and adult rodent brain and liver tissue. More specifically, researchers closely examined the conversion of alcohol to acetaldehyde (AcHO) -- a highly reactive and toxic alcohol metabolite -- in the human prenatal brain.

"The public gets outraged when they hear about crack babies," observed Thomas R. Hinds, research associate professor at the University of Washington, "but are relatively blasé about children born with alcohol-induced birth defects. The more that we as scientists can substantiate the links between prenatal alcohol exposure and Fetal Alcohol Effects and the more severe Fetal Alcohol Syndrome, the more likely the public will accept it as fact."

The first step in the metabolism of alcohol is its conversion to acetaldehyde (AcHO). AcHO belongs to a class of compounds called aldehydes (such as formaldehyde, a disinfectant and preservative), and is well known as a highly reactive and toxic chemical that can damage the cells of all living things. Normally, the liver is responsible for detoxifying the body from alcohol; alcohol is converted to AcHO in the liver, which is then rapidly metabolized to acetate, which is then further metabolized by tissues outside of the liver. Generally, there is very little AcHO in the blood of people drinking alcohol, even when blood alcohol levels are quite high. However, AcHO that may reach the blood is blocked from entering the brain by an actively metabolizing blood brain barrier. Therefore, if AcHO is to be found in the brain, it is most likely generated there and can do its damage there. This study suggested that the prenatal brain metabolizes alcohol differently that the adult brain.

"When a pregnant women drinks an alcoholic beverage," explained Mont R. Juchau, professor of pharmacology at the University of Washington School of Medicine and lead author of the study, "a part of the alcohol will pass across her placenta and enter fetal tissues, including the fetal brain. When the alcohol is converted to the highly toxic acetaldehyde in the brain tissues, it can then disrupt normal brain development. Because the cells of the human prenatal brain are rapidly dividing and rapidly differentiating, they are particularly susceptible to the damaging effects of toxic chemicals. Effects produced during this stage of development are often permanent or semi-permanent rather than transient, impacting postnatal mental function, behavior and capacity to control muscular movements."

This study focused on three enzymes known to be responsible for converting alcohol to AcHO: alcohol dehydrogenase, cytochrome P4502E1, and catalase/peroxidase. Prior to the study, researchers believed that there was little alcohol metabolism in the brain and, therefore, little or no aldehydes to be found in brain tissues.

"Based on previous studies from many laboratories," explained Juchau, "we did not expect to observe a high rate of accumulation of acetaldehyde from ethyl alcohol in human prenatal brain tissues. In fact, we did not know whether we would be able to observe a detectable accumulation at all. Therefore, we were surprised to see a rate that was approximately 20 percent of that seen with adult liver tissues, where the rate is very rapid."

These results indicate that the prenatal brain can produce significant quantities of AcHO. The prenatal brain is also much more active than expected. Considering the extremely toxic nature of AcHO, its unexpectedly high and rapid accumulation in the developing fetal brain following alcohol ingestion has important mental, neurobehavioral and neuromotor implications.

"The more that the public learns about the toxic nature of acetaldehyde," said Hinds, "then the less likely they will be willing to put the unborn in jeopardy by drinking alcoholic beverages."

Researchers also found that the three enzymes examined contributed surprisingly little to the conversion process. Instead, a totally unsuspected class of enzymes - alcohol oxidase - was apparently involved in the metabolism of alcohol in humans. Alcohol oxidase uses molecular oxygen (like that found in air) and combines it with two hydrogens from ethanol to form hydrogen peroxide and acetaldehyde. Oxidase enzymes are known to catalyze the conversion of alcohol to AcHO in lower, single-celled organisms such as yeast, but have never been reported to do so in vertebrate animals such as humans.

"We hope this study will help readers better understand why drinking alcoholic beverages during pregnancy can be particularly damaging to the fetus, especially the fetal brain." explained Juchau, "We also hope to continue these studies to better characterize the oxidase enzymes found to be at work."

Hinds concurred with the planned direction of this kind of research. "In the future, I think everyone will be looking for alcohol oxidase in all sorts of tissues, and it will no doubt be found. This is the way science works." He also thinks that more work on prenatal tissue needs to be done.

"This kind of research helps us understand the metabolism of ethanol in the prenatal brain and the damage that it can do," said Hinds. "In turn, this knowledge might prevent some pregnant women from drinking and endangering their unborn child."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Richard E. Person and Alan G. Fantel of the Department of Pediatrics at the University of Washington; and Hao Chen of the Department of Pharmacology at the University of Washington. The study was funded by the National Institute of Environmental Health Sciences.

Alcoholism: Clinical & Experimental Research

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