Prenatal Alcohol: Hormone-Regulated Genes and Behavior

DESCRIPTION (provided by applicant): Children exposed to alcohol in uterofrequently exhibit behavioral problems including hyperactivity, learningdeficits, response inhibition and increased prevalence of depression. Many ofthese behavioral deficits are also observed in animal models of fetal alcoholexposure. Similar behavioral deficits occur after prenatal stress and inchildren born to mothers with subclinical hypothyroidism. This informationformed the main hypothesis of this proposal: fetal glucocorticoid and thyroidhormone milieu may contribute significantly to the deleterious consequences ofprenatal alcohol exposure.Specific Aim 1 will investigate the sub-hypotheses that relative hypothyroidismfound in the alcohol-consuming dam and its fetuses is due, at least in part, toelevated 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 theadult offspring. Specifically, we aim to determine 1) whether eliminating thealcohol-induced increase in maternal corticosterone would normalize the FAEoffspring hypothalamic-pituitary-adrenal (HPA) and thyroid (HPT) function andbehavior; 2) if prenatal or neonatal thyroid hormone supplementation wouldcorrect HPT function abnormalities and behavioral deficits of FAE offspring.Specific Aim 2 will establish a murine model of prenatal alcohol exposure sothat with the aid of transgenic mice prenatal alcohol-induced changes inthyroid hormone responsive genes can be found in a temporal, spatial and cellspecific fashion. To achieve that, we will 1) characterize the effects of fetalalcohol exposure on HPA, HPT function and specific behavioral measures inC57BL/6J mice; 2) develop transgenic mouse line which ubiquitously expressesthe reporter LacZ gene driven by thyroid-responsive DNA promoter (pTRELacZ); 3)expose pTRE-LacZ transgenic mice to alcohol in utero and determine thedevelopmental profile and specific brain region(s) of the most profound changesin thyroid hormone responsive genes; 4) carry out a microarray-baseddifferential expression analysis on the specific brain region(s) identifiedwith the help of the pTRE-LacZ transgenic mice.The long-term goal of these studies is to determine if thyroid hormonesupplementation pre- or postnatally can ameliorate the effects of ethanol onthe developing brain. Furthermore, the proposed experiments will identify knownor novel genes that are specifically responsive to thyroid hormones and showaltered expression in the developing fetal brain during ethanol exposure.