Redei E, Halasz I, Li L F, Prystowsky M B, Aird F
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104.
Endocrinology. 1993 Aug;133(2):452-60. doi: 10.1210/endo.133.2.8344191.
Exposure to ethanol in utero compromises the offspring's developing immune and endocrine systems. Persistent functional changes, particularly in T-cell-dependent aspects of immunity and in hypothalamic-pituitary-adrenal activity, are commonly seen. The present study examined the degree to which fetal alcohol exposure (FAE) during development suppressed the lymphocyte proliferative response to Concanavalin-A (Con A). We also examined the effect of maternal adrenalectomy on the expression of glucocorticoid-regulated genes and the response to Con A in FAE offspring. Con A-stimulated lymphocyte proliferation was stably suppressed (between 28-46%) in FAE males compared to isocalorically pair-fed offspring at 7, 21, 40, and 60 days of age. In contrast, lymphocyte proliferation in the immature or peripubertal FAE female was totally unaffected. In 60-day- old male rats, maternal adrenalectomy reversed the FAE-induced suppression of Con A-stimulated proliferation, but had no effect on lymphocyte proliferation. FAE increased anterior pituitary POMC (the precursor of ACTH) mRNA levels dramatically in males, and this increase was also reversed by maternal adrenalectomy. In both sexes, anterior pituitary glucocorticoid receptor mRNA levels were unaffected by prenatal alcohol exposure alone, but were significantly decreased in male and increased in female offspring of adrenalectomized dams ingesting alcohol. Furthermore, in male, but not female, offspring, hypothalamic levels of glucocorticoid receptor and CRF mRNA were increased significantly by FAE alone or in combination with maternal adrenalectomy. In female, but not male, offspring, maternal adrenalectomy with concomitant alcohol exposure increased anterior pituitary POMC mRNA levels compared to that in sham/pair-fed offspring. In summary, FAE induced a gender-specific impairment of Con A-stimulated lymphocyte proliferation. This deficit is present both before and after puberty, demonstrating its stability into adulthood. Furthermore, in males, maternal adrenalectomy reversed these FAE-induced deficits in T-cell function as well as the effect of FAE on anterior pituitary POMC expression. This supports the hypothesis that maternal adrenal hormones participate in the immunosuppressive "imprinting" of the FAE fetus and are, therefore, causally implicated in the sexually dimorphic T-cell dysfunction found in FAE offspring.
子宫内接触乙醇会损害后代正在发育的免疫和内分泌系统。持续的功能变化很常见，尤其是在免疫的T细胞依赖性方面以及下丘脑-垂体-肾上腺活动方面。本研究考察了发育过程中胎儿酒精暴露（FAE）抑制淋巴细胞对刀豆蛋白A（Con A）增殖反应的程度。我们还研究了母体肾上腺切除术对糖皮质激素调节基因表达以及FAE后代对Con A反应的影响。与等热量配对喂养的后代相比，FAE雄性在7、21、40和60日龄时，Con A刺激的淋巴细胞增殖被稳定抑制（28%-46%）。相比之下，未成熟或青春期前的FAE雌性的淋巴细胞增殖完全未受影响。在60日龄雄性大鼠中，母体肾上腺切除术逆转了FAE诱导的对Con A刺激增殖的抑制，但对淋巴细胞增殖没有影响。FAE使雄性垂体前叶POMC（促肾上腺皮质激素的前体）mRNA水平显著升高，这种升高也被母体肾上腺切除术逆转。在两性中，垂体前叶糖皮质激素受体mRNA水平单独受产前酒精暴露影响不大，但在摄入酒精的肾上腺切除母鼠的雄性后代中显著降低，在雌性后代中升高。此外，在雄性而非雌性后代中，单独的FAE或与母体肾上腺切除术联合，会使下丘脑糖皮质激素受体和CRF mRNA水平显著升高。在雌性而非雄性后代中，与假手术/配对喂养的后代相比，母体肾上腺切除术伴随酒精暴露会增加垂体前叶POMC mRNA水平。总之，FAE诱导了Con A刺激的淋巴细胞增殖的性别特异性损害。这种缺陷在青春期前后均存在，表明其持续到成年期。此外，在雄性中，母体肾上腺切除术逆转了这些FAE诱导的T细胞功能缺陷以及FAE对垂体前叶POMC表达的影响。这支持了这样一种假设，即母体肾上腺激素参与了FAE胎儿的免疫抑制“印记”，因此与FAE后代中发现的性别差异T细胞功能障碍存在因果关系。
