Children exposed to alcohol in utero frequently exhibit behavioral problems including hyperactivity, learning deficits, response inhibition and increased prevalence of depression. Many of these behavioral deficits are also observed in animal models of fetal alcohol exposure. Similar behavioral deficits occur after prenatal stress and in children born to mothers with subclinical hypothyroidism. This information formed the main hypothesis of this proposal: fetal glucocorticoid and thyroid hormone milieu may contribute significantly to the deleterious consequences of prenatal alcohol exposure.
Specific Aim 1 will investigate the sub-hypotheses that relative hypothyroidism found in the alcohol-consuming dam and its fetuses is due, at least in part, to elevated maternal corticosterone suppressing the thyroid function. Subsequently, this prenatal hypothyroid state of the fetal alcohol-exposed (FAE) offspring can cause the activity and cognitive behavioral deficits in the adult offspring. Specifically, we aim to determine 1) whether eliminating the alcohol-induced increase in maternal corticosterone would normalize the FAE offspring hypothalamic-pituitary-adrenal (HPA) and thyroid (HPT) function and behavior; 2) if prenatal or neonatal thyroid hormone supplementation would correct HPT function abnormalities and behavioral deficits of FAE offspring.
Specific Aim 2 will establish a murine model of prenatal alcohol exposure so that with the aid of transgenic mice prenatal alcohol-induced changes in thyroid hormone responsive genes can be found in a temporal, spatial and cell specific fashion. To achieve that, we will 1) characterize the effects of fetal alcohol exposure on HPA, HPT function and specific behavioral measures in C57BL/6J mice; 2) develop transgenic mouse line which ubiquitously expresses the reporter LacZ gene driven by thyroid-responsive DNA promoter (pTRELacZ); 3) expose pTRE-LacZ transgenic mice to alcohol in utero and determine the developmental profile and specific brain region(s) of the most profound changes in thyroid hormone responsive genes; 4) carry out a microarray-based differential expression analysis on the specific brain region(s) identified with the help of the pTRE-LacZ transgenic mice. The long-term goal of these studies is to determine if thyroid hormone supplementation pre- or postnatally can ameliorate the effects of ethanol on the developing brain. Furthermore, the proposed experiments will identify known or novel genes that are specifically responsive to thyroid hormones and show altered expression in the developing fetal brain during ethanol exposure.
