Hormones and FAS

A low dose of thyroid hormone administered during the correct stage of pregnancy appears to protect against Fetal Alcohol Spectrum Disorder (FASD), according to new research done at the Northwestern University's Feinberg School of Medicine.

Prenatal alcohol exposure is the most widespread cause of nongenetic mental retardation in the United States, making it a critical area for study.

Fetal Alcohol Spectrum Disorder is less severe than Fetal Alcohol Syndrome (FAS), but more widespread, affecting as many as two to five percent of school-age children. Children with FASD may experience impairments in learning and memory, high rates of depression and anxiety, and social deficits, often misdiagnosed as conduct disorder.

Researcher Eva Redei and her team wanted to find out why.

“We have shown decreases in thyroid function in alcohol-drinking pregnant rats in prior studies,” explains Redei, the David Lawrence Stein Professor of Psychiatry at Northwestern. “Decreased thyroid function has also been found in alcohol-drinking women. Pregnant women need more thyroid hormone because they provide it to their fetus before the fetal thyroid gland begins functioning.”

To test whether replenishing lost thyroid hormone could reverse the effects of alcohol, Redei’s team gave pregnant rats alcohol, then administered the thyroid hormone thyroxin.

As adults, the male rats that had been exposed to alcohol in the womb were less inquisitive and had worse social memory than their healthy, alcohol-free counterparts. In the test group, where both alcohol and thyroxin were present in the rat mothers’ systems, these differences disappeared.

A Genetic Link to Autism

In addition to testing the alcohol-exposed rats’ behavior, Redei also examined the effects of alcohol and thyroxin on the rat pups’ genetics.

The researchers noticed that the effects of FASD resembled some of the symptoms of Autism Spectrum Disorder (ASD), a disorder that causes social and developmental impairments. Although ASD is not fully understood, current research suggests that the disorder occurs—at least in part—when certain genes are expressed incorrectly. To examine this, Redei selected a group of genes that has been linked to ASD in both rats and humans.

In the male rats that had been exposed to alcohol, gene expression markers for several ASD genes were found at much higher rates than in the control rats. When the rats were given thyroxin, these genetic differences disappeared along with the behavioral differences.

To bolster their idea that thyroxin deficiency plays a role in FASD and ASD, Redei’s team examined the promoter regions of these genes. A promoter region is a segment of DNA that determines when a gene will turn on or off, and therefore how much that gene will be expressed. Promoter regions can be affected by all kinds of factors—exercise or stress, toxins or vitamins in the diet, and even being in love. 

In this case, they found that these ASD gene promoters were sensitive to thyroxin. By changing the rat pups’ thyroxin levels, Redei’s team were able to change the way the rats’ genes told their brains to grow.

“During neural development, autism vulnerability genes are particularly important,” Redei said. “Alcohol during fetal development is affecting some of these same genes, and that's what we showed in this model. That suggests that perhaps the similarities of the behavioral outcome [in ASD and FASD] are not an accident.”

Gender Differences in Autism and FASD

One of the study’s interesting findings was that only the male rats exposed to alcohol in the womb showed social impairment, a finding that has been widely established by rat studies in the past. The female rats that had been exposed to alcohol, on the other hand, showed increased social activity and memory compared to the controls.

The cause of this gender difference is unknown, although scientists have some theories. In humans, autism occurs in males four times as frequently as in females, and hormone levels may be the key.

“Fetal alcohol has clear effects on the offspring that is different between males and females,” explains Redei. “Not just social behavior, but also the stress response. Females have a much higher stress response, but it returns to baseline fast. Males have a smaller stress response, but it is prolonged.”

Unfortunately, not much data exists yet on how gene expression varies between males and females.

“Sex differences have been ignored for a long time in medicine,” Redei said. “It's acknowledged only when it intrudes into your space, when you can't ignore it, such as in autism, or depression, which is much more prevalent in women than men.”

New Treatments on the Horizon

Although more study is required, Redei is hopeful that her team’s research could someday lead to new treatments for unborn or newborn children.

“The best part of the study is that the thyroxin treatment is very, very promising,” Redei said. “Our goal is to know what alcohol and then thyroxin are doing, for which this study is a clue. Maybe there is an implication for a new treatment here, even if it is not thyroxin, but thyroxin-regulated pathways that act during neurodevelopment to normalize behavior. And so that really suggests what we knew before: thyroid hormones are very important in neurodevelopment.”

Even if thyroxin itself is the ideal treatment, Redei warns that it wouldn’t allow pregnant women to drink guilt-free. “Too much thyroxin crosses into the fetus from the mother,” she explains. “That would suppress the development of the fetus' own thyroid function. It has much less detrimental effects on neurodevelopment than if there is not enough thyroid hormone, but it's still not good.”

A developing baby's brain is most vulnerable to alcohol during the late first trimester and early second trimester, often before many women even know they are pregnant. Expecting mothers who inadvertently drink alcohol before knowing they are pregnant could seek such treatment. Moreover, this offers hope for the children of mothers who are unable to control their alcohol consumption.

“No responsible physician would give a large dose of thyroxin to a pregnant mother," Redei said. "But if the levels of the pregnant mother are below the levels expected and a small dose would be helpful, that's a different question.”

Learn More: