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.
| Aird, F; Clevenger, C V; Prystowsky, M B et al. (1993) Corticotropin-releasing factor mRNA in rat thymus and spleen. Proc Natl Acad Sci U S A 90:7104-8 |
| Redei, E; Halasz, I; Li, L F et al. (1993) Maternal adrenalectomy alters the immune and endocrine functions of fetal alcohol-exposed male offspring. Endocrinology 133:452-60 |
| Redei, E (1992) Immuno-reactive and bioactive corticotropin-releasing factor in rat thymus. Neuroendocrinology 55:115-8 |
