PRENATAL ALCOHOL EXPOSURE--IMMUNE/ENDOCRINE INTERACTIONS

母亲在怀孕期间饮酒的不良影响包括 据报道，患有胎儿酒精的儿童存在严重的免疫缺陷， 与年龄匹配的对照组相比。 胎儿动物模型 酒精暴露（FAE）已经证明，酒精暴露在过去的 怀孕两周会产生长期的T细胞缺陷， 功能，主要是在男性后代。 然而，迄今为止， 评估了怀孕期间饮酒的机制 会损害后代的免疫功能 饮酒会改变母体激素的产生， 影响胎儿免疫功能的发育。 的观察结果 成年FAE雄性大鼠中受抑制的T细胞功能被以下方法消除： 母体肾上腺切除术表明母体肾上腺激素 参与FAE胎儿的免疫抑制“印记”。 因此，实验的目的是集中在表征激素 负责这种产前性别二态效应的成分 酒精暴露对T细胞功能的影响 本提案寻求：1. 描述酒精暴露对 肾上腺/性腺类固醇的分泌特征和血浆水平 完整和肾上腺切除的孕鼠整个妊娠期; 2. 以确定母亲肾上腺切除术和产前酒精的影响 暴露对胎儿胸腺功能发育的影响 胎儿，并对选定的细胞和分子参数的T细胞 功能，在成年男性和女性后代的肾上腺切除酒精- 消耗水坝; 3. 以确定是否有糖皮质激素或其他 已知会影响免疫功能的类固醇激素， 在具体目标1中确定的酒精中毒中升高， 负责FAE男性的免疫抑制“印记”， 女性胎儿，以及这种类固醇是否影响胎儿胸腺发育 直接和性别特异性，或通过长期的， 糖皮质激素、雌激素或 后代中的雄激素受体;以及4. 最后确定是否 产前给予脱氢表雄酮，一种弱雄激素， 糖皮质激素受体拮抗剂，具有已知的抑制作用 特定的疾病过程，将消除免疫抑制作用 产前酒精暴露对男性后代的影响

Adverse effects of maternal alcohol consumption during pregnancy include the severe immunodeficiencies reported in children with fetal alcohol syndrome compared to age matched controls. Animal models of fetal alcohol exposure (FAE) have proved that alcohol exposure during the last two weeks of gestation can produce long-lasting defects of T-cell function, primarily in male offspring. However, no studies to date have assessed the mechanism by which alcohol consumption during pregnancy compromises the offspring's immune function. Alcohol consumption alters production of maternal hormones that can affect the development of fetal immune function. The observation that suppressed T-cell function in adult FAE male rat was abolished by maternal adrenalectomy suggests that maternal adrenal hormones do participate in the immunosuppressive "imprinting" of the FAE fetus. Thus, experiments are designed to focus on characterizing the hormonal components responsible for this sexually dimorphic effect of prenatal alcohol exposure on T-cell function. This proposal seeks: 1. to delineate the effect of alcohol exposure on the secretory profile and plasma levels of adrenal/gonadal steroids in the intact and adrenalectomized pregnant rat throughout gestation; 2. to determine the effect of maternal adrenalectomy and prenatal alcohol exposure on fetal development of thymic functions in male and female fetuses, and on selected cellular and molecular parameters of T-cell function, in adult male and female offspring of adrenalectomized alcohol- consuming dams; 3. to determine whether glucocorticoids, or any other steroid hormones that are known to affect immune function and were found to be elevated in alcoholism as established in Specific Aims 1, are responsible for the immunosuppressive "imprinting" of the FAE male and female fetus, and whether this steroid affects fetal thymic development directly and gender-specifically, or through long-term, sexually dimorphic changes in the expression of glucocorticoid, estrogen or androgen receptors in the offspring; and 4. finally to determine whether prenatal administration of dehydroepiandrosterone, a weak androgen and glucocorticoid receptor antagonist with known inhibitory effects on specific disease processes, will eliminate the immunosuppressive effect of prenatal alcohol exposure on the male offspring.