Prenatal alcohol: Hormone-regulated genes and behavior

产前酒精：激素调节的基因和行为

• 批准号: 7856231
• 负责人: Eva E Redei
• 金额: $ 4.17万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856231
• 关键词: Adult; Adult Children; Affect; Alcohol consumption; Alcohols; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain region; Child; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Diagnosis; Dose; Embryo; Embryonic Development; Emotional; Ethanol; Exhibits; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Funding; Gene Expression; Genes; Glucocorticoid Receptor; Goals; Grant; Growth Associated Protein 43; High Prevalence; Hormonal; Hormones; Human; Hyperactive behavior; Hypothalamic structure; Hypothyroidism; Impaired cognition; Intervention; Learning; Learning Disorders; Memory; Mothers; Neonatal; Perinatal; Pituitary Gland; Placenta; Pregnancy; Prevalence; Problem behavior; Rattus; Resistance; Role; Second Pregnancy Trimester; Supplementation; Swimming; Testing; Third Pregnancy Trimester; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin-Releasing Hormone; Thyroxine; Time; Treatment Protocols; Uterus; Youth; alcohol consumption during pregnancy; alcohol exposure; base; behavior test; biobehavior; cognitive function; conditioned fear; depression; fetal; morris water maze; neurogranin; offspring; postnatal; pregnant; prenatal; protein expression; response; thyroid transcription factor 1; young adult

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.

描述（由申请人提供）：产前接触酒精的儿童经常表现出行为问题，包括注意力缺陷/多动障碍（ADHD）和学习障碍；在诊断为胎儿酒精谱系障碍的青少年中，其患病率接近60%。患有轻度甲状腺功能低下症或对甲状腺激素有抵抗力的母亲所生的孩子中，有很大一部分也被诊断为多动症。因此，产前酒精暴露、甲状腺功能和认知障碍之间似乎有着密切而神秘的关系。目的是阐明围产期甲状腺激素环境在胎儿酒精暴露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甲状腺功能。我们还发现，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。由于产前甲状腺素（T4）的使用逆转了胎儿酒精暴露（FAE）后代的行为缺陷，母亲甲状腺功能的抑制似乎导致了这些行为异常。我们假设饮酒孕妇的甲状腺激素水平降低，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：给予不同剂量的T4对a)限制或调节胎儿甲状腺激素暴露的子宫和胎盘基因表达的影响；b)胎儿大脑特定区域甲状腺激素调控基因的表达；具体目标2。确定T4的剂量，扭转FAE的行为后果，但不改变成人甲状腺功能不利；具体目标3。发展酒精暴露后的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与母胎甲状腺功能之间的相互作用，作为产前乙醇诱导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。