Prenatal alcohol: Hormone-regulated genes and behavior

描述(申请人提供)：产前接触酒精的儿童经常出现行为问题，包括注意力缺陷/多动(ADHD)障碍和学习障碍；在被诊断为胎儿酒精谱系障碍的青少年中，这种问题的患病率接近60%。母亲患有轻度低甲状腺素血症或对甲状腺激素有抵抗力的孩子中，有很大一部分也被诊断为ADHD。因此，产前酒精暴露、甲状腺功能和认知障碍之间似乎存在着密切而神秘的关系。这项建议的目的是阐明围产期甲状腺激素环境在酒精暴露的胎儿大鼠认知功能中的作用。在之前的资助期间，我们已经表明，饮酒怀孕的水坝抑制了甲状腺功能。我们还表明，它们的成年后代表现出甲状腺功能异常、绝望样行为和认知障碍。母亲甲状腺功能的抑制似乎是导致这些行为异常的原因，因为产前给予甲状腺素(T4)可以逆转胎儿酒精暴露(FAE)后代的行为缺陷。我们推测，饮酒妊娠母鼠的甲状腺激素环境降低，通过胎盘影响胎儿大脑中甲状腺激素调节基因的表达，从而影响成年FAE后代的认知和情感行为。基于这一假设，我们将研究：特定目的1.酒精摄入后给予不同剂量的T4对以下方面的影响：a)限制或调节胎儿甲状腺激素暴露的子宫和胎盘基因的表达；b)胎儿大脑特定区域甲状腺激素调控基因的表达；特定目的2.确定逆转FAE行为后果但不会对成人甲状腺功能产生不利影响的T4剂量；特定目标3.建立酒精暴露后围产期甲状腺激素治疗范例，旨在找到一种逆转FAE行为缺陷并使成年FAE后代甲状腺功能正常化的方法。我们的长期目标是了解酒精和母胎甲状腺功能之间的相互作用，作为产前酒精导致后代行为缺陷的潜在机制。我们预计，在FAE动物模型中成功的T4治疗方案可能会在临床试验中实施。

DESCRIPTION (provided by applicant): 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.