Departments of Psychiatry and Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Mol Cell Neurosci. 1993 Aug;4(4):343-53. doi: 10.1006/mcne.1993.1044.
Maternal ethanol consumption has deleterious effects on the offspring's neuroendocrine and T-cell-dependent functions. Chronic alcohol consumption in adulthood has also been associated with activated hypothalamic-pituitary-adrenal (HPA) function and immunosuppression which is demonstrable at the T-cell level. Our aim was to establish whether prenatal alcohol exposure alters the neuroendocrine and immune responses to chronic alcohol challenge in adult male and female offspring. Adult male rats placed on a liquid alcohol diet for 5 weeks had significantly decreased thymus weight, hypertrophied adrenals, and elevated plasma ACTH and corticosterone levels. Splenic lymphocyte Concanavalin A (Con A)-stimulated proliferation in the ethanol-treated rats was decreased compared to that in pair-fed controls. Thus, prolonged alcohol exposure activated the HPA axis and suppressed T-cell function. The effects of prenatal alcohol exposure, as a predispositional factor, on the HPA axis and on the T-cell functions of adult chronic alcohol-exposed rats were examined in the offspring of dams fed ethanol (FAE) or an isocaloric liquid (PF) diet during the last 2 weeks of gestation. The adult offspring of both sexes and prenatal treatment groups were then placed on an alcohol-containing liquid diet for 5 weeks. Fetal alcohol exposure decreased anterior pituitary proopiomelanocortin mRNA levels and increased glucocorticoid receptor (GR) mRNA levels in males and decreased GR mRNA levels in females. There were no differences in hypothalamic CRF mRNA and GR mRNA levels between the prenatal treatment groups. There was no significant difference in Con A-stimulated lymphocyte proliferation between FAE and PF males. However, FAE females showed Con A-stimulated lymphocyte proliferation significantly higher than those of all other groups, including pair-fed females. Prostaglandin E(2) (PGE(2)) suppressed lymphocyte proliferation to a lesser degree in FAE males than in any other group. Furthermore, T-cell response to Con A was enhanced by indomethacin, a prostaglandin biosynthesis inhibitor, in FAE males suggesting that increased prostaglandin synthesis may occur in FAE males after chronic alcohol exposure. Increased levels of endogenous PGE(2) could also be inferred from the enhanced levels of interleukin-2 receptor alpha (IL-2Ralpha) mRNA in activated lymphocytes of male but not of female FAE offspring compared to PF. In summary, the results of this study demonstrate that prenatal alcohol exposure leads to a specific HPA-related vulnerability in males to the deleterious effects of ethanol in adulthood. Although prenatal alcohol did not further aggravate the effects of chronic alcohol exposure on lymphocyte proliferation response to Con A in adult male offspring, altered T-cell responses could be unmasked.
母体乙醇摄入对后代的神经内分泌和 T 细胞依赖功能有有害影响。成年期慢性饮酒也与激活下丘脑-垂体-肾上腺 (HPA) 功能和免疫抑制有关，这种抑制可在 T 细胞水平上表现出来。我们的目的是确定产前酒精暴露是否会改变成年雄性和雌性后代对慢性酒精挑战的神经内分泌和免疫反应。成年雄性大鼠接受 5 周的液体酒精饮食后，胸腺重量显著减轻，肾上腺肥大，血浆 ACTH 和皮质酮水平升高。与配对喂养对照组相比，乙醇处理组的脾淋巴细胞刀豆球蛋白 A (Con A) 刺激增殖减少。因此，长期饮酒激活了 HPA 轴并抑制了 T 细胞功能。在妊娠最后 2 周接受乙醇 (FAE) 或等热量液体 (PF) 饮食的母体后代中，检查了产前酒精暴露作为易感性因素对成年慢性酒精暴露大鼠的 HPA 轴和 T 细胞功能的影响。然后，所有性别和产前处理组的成年后代都被置于含有酒精的液体饮食中 5 周。胎儿酒精暴露降低了雄性前垂体促黑皮质素原 mRNA 水平并增加了糖皮质激素受体 (GR) mRNA 水平，而雌性 GR mRNA 水平降低。产前处理组之间下丘脑 CRF mRNA 和 GR mRNA 水平没有差异。FAE 和 PF 雄性之间 Con A 刺激的淋巴细胞增殖没有差异。然而，FAE 雌性的 Con A 刺激的淋巴细胞增殖明显高于其他所有组，包括配对喂养的雌性。与任何其他组相比，FAE 雄性的前列腺素 E2 (PGE2) 对淋巴细胞增殖的抑制作用较小。此外，在 FAE 雄性中，前列腺素生物合成抑制剂吲哚美辛增强了 T 细胞对 Con A 的反应，表明慢性酒精暴露后 FAE 雄性可能会发生前列腺素合成增加。与 PF 相比，FAE 雄性激活淋巴细胞中白细胞介素 2 受体 alpha (IL-2Ralpha) mRNA 的水平增加，也可以推断内源性 PGE2 水平升高。总之，这项研究的结果表明，产前酒精暴露导致雄性对成年期乙醇的有害影响产生特定的与 HPA 相关的脆弱性。尽管产前酒精并没有进一步加重慢性酒精暴露对成年雄性后代对 Con A 淋巴细胞增殖反应的影响，但改变的 T 细胞反应可能会显现出来。
