Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat.
The effects of glucocorticoid (GC) treatment on the mature immune and neuroendocrine system are known to be reversible. However, prenatal GC exposure may have irreversible consequences on the development of the newborn. In this study, possible long-lasting effects of short-term prenatal GC treatment were examined on the developing thymus, spleen and hypothalamo-pituitary adrenal axis (HPA axis). Female rats were given dexamethasone (DEX, 400 micrograms, i.p.) on day 17 and 19 of pregnancy and offspring was studied at several time intervals (1-20 days) after birth, for examination of thymus, spleen, hypothalamus and blood plasma. Examination of thymus and spleen revealed that prenatal exposure to DEX resulted in decreased T cell numbers in thymus and spleen on day 1 after birth. Thymus regeneration after DEX exposure both during pregnancy and in adult life was completed after 24 days. However, the kinetics of regeneration of the thymi after prenatal DEX exposure were different from that seen after DEX in adult life. Whereas DEX treatment during pregnancy resulted in an increased ratio of CD4+/CD8- thymocytes over CD4-/CD8+ thymocytes compared to control groups on day 7 and day 20 after birth (time X treatment interaction; P < 0.05), DEX treatment in adult life did not change this ratio. T cell numbers in the spleen were significantly decreased at all neonatal ages studied. Regarding the hypothalamus, prenatal exposure to DEX altered the pattern of neonatal changes in peptide expression in corticotropin-releasing hormone neurons, with a selective reduction in CRH storage in the median eminence (7 and 9 days after birth) and an increase in AVP storage (9 and 20 days after birth). The ratio of AVP over CRH was significantly increased at all developmental ages studied. No effects were seen on basal ACTH and corticosterone levels in plasma. In conclusion, the kinetics of thymus regeneration after DEX exposure during pregnancy were different from that seen after DEX exposure in adult life. Prenatal DEX exposure also seemed to delay the migration of T cells into the spleen. Furthermore, prenatal DEX treatment exerted major effects on hypothalamic CRH neurons that maintained for at least 20 days after birth, which points towards an enhanced stress responsiveness of the HPA axis in later life.
Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, Netherlands.
J M
JM
Bakker
E D
ED
Schmidt
H
H
Kroes
A
A
Kavelaars
C J
CJ
Heijnen
F J
FJ
Tilders
E P
EP
van Rees
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000648:ultrastructure; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000648:ultrastructure; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000196:embryology* / Q000276:immunology*; D007031:Hypothalamus / Q000166:cytology / Q000276:immunology / Q000648:ultrastructure; D007107:Immune System / Q000187:drug effects* / Q000196:embryology* / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000648:ultrastructure; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D013997:Time Factors
D016693:Receptors, Antigen, T-Cell, alpha-beta; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone