By David N. Leff

From beer to bourbon, every bottle of booze sold in the U.S. must carry on its label, in capital letters, this caveat:


When that risk becomes a fact, its newborn victim is seen as suffering from fetal alcohol syndrome (FAS).

That syndrome's litany of physical and behavioral abnormalities reflects the multiple derailments of development in utero by ingested ethanol's little-understood effects on growing tissue.

"What happens in FAS," said bone-cell biologist Leonard Rifas, at Washington University, in St. Louis, "is that there are physical dysmorphias -- intrauterine growth retardation, craniofacial anomalies and intellectual impairment postnatally."

The visible stigmata of FAS in a newborn infant, he went on, "include small eyes and ears, reduced growth of the midfacial and maxillary [jaw] bones, poorly developed upper lips and noses, epicanthal folds around the eyes, frequently cleft palate, small heads."

Obstetricians, neonatal pediatricians and delivery-room nurses used to refer to these blemished babies as "flks" -- funny-looking kids. In the present day of political correctitude, they tend to prefer "dysmorphic infants."

FAS is far from rare. Maternal consumption of ethanol degrades the mental and physical endowments of at least three in every 1,000 infants born in the U.S. -- about 12,000 each year -- and one in 300 born elsewhere in the Western world.

Because some of these FAS hallmarks are borderline, pointed out physician and research biochemist Dwight Towler, "When a clinician looks at a baby who has those findings -- its physiognomy doesn't look quite normal -- he or she might go back and ask the mother about her drinking history, her ethanol exposures during first-trimester gestation," in order to support a diagnosis of FAS. He added: "There is significant correlation between fetal alcohol exposure, particularly in a binge-drinking pattern, and these subtle craniofacial abnormalities."

Towler and Rifas are co-lead authors of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated July 8, 1997, titled: "Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos."

Towler's research focuses on the msx2 gene, which regulates other genes that are expressed during craniofacial development in utero. "It's a key regulator of craniofacial morphogenesis," he told BioWorld Today.

"Our PNAS paper," Towler added, "reports the first interactions between a homeodomain regulator of craniofacial development and the effects of alcohol on that interaction. Msx gene family members encode homeo proteins, which are transcription factors that control key development processes.

Chasing Down Ethanol's Prenatal Ravages

"There are some human disorders," Towler continued, "called craniosynostosis [premature closure of the skull bones]. Those have been mapped to a select subset of genes, including msx2, so my biochemical analysis plus the genetic analysis of a colleague, and now this collaborative effort with the Rifas-Avioli bone and mineral disease group, have nailed the relationship between homeodomain regulators and dysmorphic characterization of the developing fetal face and skullcap."

The PNAS paper's senior author is Louis Avioli, chief of bone and mineral diseases at Washington University.

Not all FAS hallmarks are apparent at birth. "Some behavioral abnormalities," Towler pointed out, "in terms of irritability, hyperactivity, attention spans, intellectual development, are diagnosed later in life -- around age five, when a child starts school."

Rifas told BioWorld Today how his group generated a FAS mouse model:

"First, we mated the mice. Then, at day eight of gestation, we injected the animals with enough alcohol to make them very drunk. Next, at day 11, we took the embryos and examined them for the expression of the msx2. For this, we used in situ hybridization probes in a whole embryo to see all the sites where the gene is being expressed -- in the normal embryo, and in embryos from the alcoholic, ethanol-treated mothers.

"One probe turned the site where the gene was being expressed blue. We saw none of this in embryos from the alcohol-treated mother. So that told us that the gene wasn't on in vivo in this FAS animal."

In another experiment, Rifas continued, "We transfected bone cells with the msx2 gene's promoter. This was attached to a luciferase gene, which lit up when the msx2 promoter turned on."

They did the same thing with an irrelevant cytomegalovirus (CMV) gene, also hooked to the luciferase.

"What we found," Rifas said, "was that as we increased the amount of alcohol, we got less and less luciferase glow. And with the CMV, no change. So we knew this was happening specifically with the msx2 promoter."

Acne Medicine's Teratogenic Danger Was A Clue

What prompted the Washington University team's investigation of fetal alcohol damage was earlier research elsewhere into the teratogenic effects of retinoic acid, the remedy of choice against acne.

"Many people," Towler observed, "have started to look for the effects of alcohol on molecules of retinoic acid, which, like fetal alcohol, affects craniofacial development. The retinoids also regulate msx2 gene expression in bone cells generally.

"One of the reasons you don't give these pimple remedies to pregnant women," Towler went on, "is that the retinoids are absorbed in the skin, and cause terrible teratogenic effects in the developing fetus. Quite often," he pointed out, "you'll get severe acne in the reproductive age group, so you want to make sure the young women are on birth control pills at the time they're taking retinoids."

High on Towler's research agenda is "looking at the effect of other teratogens besides ethanol on msx2 expression and action."

Rifas observed: "I think everybody has always said: 'You should not drink large amounts of alcohol if you're pregnant,' but nobody knew why not. I think what we're doing here," he continued, "is, we've come across the 'how' of what alcohol is doing in utero.

"What we'll be doing next," he concluded, "is open up a door to examine why not. 'If you do this, this is what's going to happen. And who knows if it can be fixed or not. When we know what's going on, maybe yes, maybe no. That's a very big speculation at this time." *