Children exposed to alcohol prenatally frequently exhibit behavioral problems including attention deficit/hyperactivity (ADHD) disorder and learning deficit;the prevalence of which is close to 60% among youth diagnosed with fetal alcohol spectrum disorder. A large percentage of children born to mothers with mild hypothyroxinemia or with resistance to thyroid hormones are also diagnosed with ADHD. Thus, there seems to be a close and enigmatic relationship between prenatal alcohol exposure, thyroid function and cognitive impairment. The goal of this proposal is to elucidate the role of perinatal thyroid hormonal milieu in the cognitive function of the fetal alcohol exposed rat. During the previous funding period, we have shown that alcohol consuming pregnant dams have suppressed thyroid function. We have also shown that their adult offspring exhibits thyroid function abnormalities, despair-like behavior and cognitive impairments. The suppressed maternal thyroid function seems to cause these behavioral abnormalities, since prenatal thyroxine (T4) administration reversed the behavioral deficits in the fetal alcohol exposed (FAE) offspring. We hypothesize that the decreased thyroid hormone milieu of the alcohol consuming pregnant dam affects, via the placenta, the expression of thyroid hormone-regulated genes in the fetal brain, and thereby impact the cognitive and emotional behavior of the adult FAE offspring. Based on this hypothesis, we will investigate:
Specific Aim 1. The effects of administering different doses of T4 to alcohol consuming dams on a) the expression of uteral and placental genes that restrict or modulate thyroid hormone exposure of the fetus;and b) on the expression of genes regulated by thyroid hormones in specific regions of the fetal brain;
Specific Aim 2. Determine a dose of T4 that reverses the behavioral consequences of FAE but does not alter the adult thyroid function adversely;
Specific Aim 3. Develop perinatal thyroid hormone treatment paradigms subsequent to the alcohol exposure, aimed at finding one that reverses the FAE behavioral deficits and normalizes the thyroid function of the adult FAE offspring. Our long-term goal is to understand the interaction between alcohol and the maternal-fetal thyroid function, as a potential mechanism by which prenatal ethanol induces behavioral deficits in the offspring. We anticipate that T4 treatment protocols successful in the animal model of FAE can potentially be implemented in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013452-07
Application #
7798572
Study Section
Special Emphasis Panel (ZRG1-BBBP-J (02))
Program Officer
Hereld, Dale
Project Start
2002-03-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$336,353
Indirect Cost
Name
Northwestern University at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tunc-Ozcan, Elif; Ullmann, Timothy M; Shukla, Pradeep K et al. (2013) Low-dose thyroxine attenuates autism-associated adverse effects of fetal alcohol in male offspring's social behavior and hippocampal gene expression. Alcohol Clin Exp Res 37:1986-95
Shukla, Pradeep K; Sittig, Laura J; Ullmann, Timothy M et al. (2011) Candidate placental biomarkers for intrauterine alcohol exposure. Alcohol Clin Exp Res 35:559-65
Sittig, Laura J; Shukla, Pradeep K; Herzing, Laura B K et al. (2011) Strain-specific vulnerability to alcohol exposure in utero via hippocampal parent-of-origin expression of deiodinase-III. FASEB J 25:2313-24
Sittig, L J; Herzing, L B K; Shukla, P K et al. (2011) Parent-of-origin allelic contributions to deiodinase-3 expression elicit localized hyperthyroid milieu in the hippocampus. Mol Psychiatry 16:786-7
Shukla, Pradeep K; Sittig, Laura J; Andrus, Brian M et al. (2010) Prenatal thyroxine treatment disparately affects peripheral and amygdala thyroid hormone levels. Psychoneuroendocrinology 35:791-7
Sittig, Laura J; Redei, Eva E (2010) Paternal genetic contribution influences fetal vulnerability to maternal alcohol consumption in a rat model of fetal alcohol spectrum disorder. PLoS One 5:e10058
Wilcoxon, Jennifer Slone; Nadolski, Gregory J; Samarut, Jacques et al. (2007) Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha. Behav Brain Res 177:109-16