Fetal alcohol spectrum disorders and autism spectrum disorder share common molecular vulnerabilities

(Press-News.org) Contact: Eva E. Redei
e-redei@northwestern.edu
312-908-1791
Northwestern University Feinberg School of Medicine

Contact: R. Thomas Zoeller
tzoeller@bio.umass.edu
413-545-2088
University of Massachusetts Amherst Alcoholism: Clinical & Experimental Research
Fetal alcohol spectrum disorders and autism spectrum disorder share common molecular vulnerabilities Both Fetal Alcohol Spectrum Disorders and Autism Spectrum Disorder are neurodevelopmental in origin.
A new rodent study has found that these disorders share common molecular vulnerabilities.
Findings also suggest that a low dose of the thyroid hormone thyroxin (T4) to the pregnant mothers appears to alleviate some of the effects of alcohol exposure on their offspring.

The term Fetal Alcohol Spectrum Disorders (FASD) refers to a continuum of disabilities caused by prenatal alcohol exposure. Some of the most debilitating symptoms of FASD are social behavioral deficits, which overlap with symptoms of Autism Spectrum Disorder (ASD). Both of these compendium disorders are neurodevelopmental in origin. A new rodent study has found that these disorders share common molecular vulnerabilities, and that a low dose of the thyroid hormone thyroxin (T4) to the pregnant mothers appears to alleviate some of the effects of alcohol exposure.

Results will be published in the November 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"Disorders that occur in infancy and childhood are considered neurodevelopmental in origin," said Eva E. Redei, the David Lawrence Stein Professor at Northwestern University Feinberg School of Medicine as well as corresponding author for the study. "ASD is thought to be triggered by genetics, prenatal and perinatal environmental factors, and other undefined causes. Autistic children and adults have differing degrees of difficulties with initiating social interactions with others, and also seem to have a deficit in social sense. Similarly, children and adults with FASD have deficits in social skills, and show unresponsiveness to social cues, a lack of reciprocal friendships, a lack of tact, and difficulty in cooperating with peers."

"This work is a continuation of a line of research that the investigators have pursued for many years," noted R. Thomas Zoeller, a professor of biology at the University of Massachusetts Amherst. "It should be recognized that comparing FASD with ASD is difficult in itself because ASD has no known single cause and there are no biochemical markers in blood that 'identify' the disorder; ASD is defined behaviorally. This is also somewhat true of FASD, but part of its definition is a history of maternal alcohol consumption."

"Maternal hypothyroidism and maternal alcohol consumption have similar consequences on the offspring, particularly related to learning and memory abnormalities in both animals and humans," added Redei. "In a previous study, we administered a much larger dose of thyroid hormone to the alcohol-consuming rat mothers, and found that their learning and memory deficit was eliminated by this treatment. In this study, we wanted to find the smallest dose of thyroid hormone that effectively reverses behavioral consequences of FASD."

Redei and her colleagues provided four different diets – standard lab chow, pair-fed nutritional chow, alcohol, or alcohol supplemented with 0.3, 1.5, or 7.5 mg of T4 per liter – to groups of Sprague-Dawley rats during pregnancy. In the adult offspring, social behavior and memory were tested; in addition, measures were recorded for plasma total T4, free T3, and thyroid-stimulating hormone as well as hippocampal expression of genes known to be causally related to ASD.

"We found that male offspring of mothers who consumed alcohol during pregnancy interacted much less with a young, non-threatening animal than the offspring of control mothers," said Redei. "When we investigated ASD-associated candidates in the brains of these offspring, we found that prenatal alcohol exposure altered the levels of these markers in the male brain. Furthermore, administering low dose thyroid hormones to the alcohol-consuming mother rat reversed the effects on social deficits and altered levels of ASD-associated gene candidates in the brains of the offspring."

"Because of the overlap in behavioral deficits between FASD and ASD – both in humans and in animals – the current findings are very important to both of these fields," said Zoeller. "There are several studies showing that FASD children exhibit similar behaviors to children with ASD, so the authors of the current study are quite right to make these comparisons experimentally. In addition, we know that thyroid hormone has similar effects on humans and animals, so there is high confidence that the studies described here are relevant to human – and public – health. Because ASD is increasing in incidence and prevalence, the current studies are also important because it points to a potential biochemical marker – thyroid hormone – that could be used to identify children that may be at risk for ASD."

Redei was hesitant to draw parallels between her rodent findings and human applications. "Caution is needed to interpret these results for their relevance to treatments in human FASD and ASD," she said. "Human studies are needed to establish that the parallel seen in this animal model – that FASD and ASD may share some common mechanism of disturbance in neurodevelopment – exists for these diseases on a human level. Hopefully these research findings, with more work, can translate into novel treatment strategies for these devastating disorders."

Zoeller agreed. "These are important new experimental findings that will not be fully understood for some years," he said. "However, they will be the basis for a more effective research direction that could ultimately help children with these conditions. Results should encourage pregnant women – or women considering starting a family – to ensure that her thyroid gland is working properly. Moreover, the study might suggest that pregnant women have thyroid tests done at her initial prenatal checkup. However, the use of thyroid hormone supplementation during pregnancy must be very carefully managed because other studies show that an overdose of thyroid hormone could also produce adverse effects."

### Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Low Dose Thyroxine Attenuates Autism Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression," were Elif Tunc-Ozcan, Timothy M. Ullmann, and Pradeep K. Shukla of the Department of Psychiatry and Behavioral Sciences at The Asher Center at Northwestern University Feinberg School of Medicine. The study was funded by the National Institutes of Health. This release is supported by the Addiction Technology Transfer Center Network at http://www.ATTCnetwork.org.