Dexamethasone, beta-estradiol, and 2,3,7,8-tetrachlorodibenzo-p-dioxin elicit thymic atrophy through different cellular targets.
The effects of single doses of dexamethasone (DEX), beta-estradiol-17-valerate (E2), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the kinetics of thymic atrophy and related bone marrow and thymocyte phenotype alterations were examined. The results imply differences in the mechanisms by which these compounds act. Of the three compounds, DEX induced maximal atrophy by 3 days with complete recovery by Day 12. At the point of maximal atrophy, the RAG-1+TdT+CD4+8+3int thymocyte population was proportionately the most depleted. In contrast, TCDD and E2 caused maximal thymic atrophy by Day 12. E2 treatment, like DEX, resulted in a preferential decrease in the RAG-1+TdT+CD4+8+3int population, but unlike DEX, this decrease persisted. TCDD-induced thymic atrophy resulted from a proportional loss of all classes of thymocytes. There was no significant relative reduction of TdT+RAG-1+ cells by TCDD in the thymus. A slow and persistent reduction of TdT and RAG-1 in bone marrow by both TCDD and E2 contrasted with the rapid reduction and quick recovery of these markers in marrow from DEX-treated animals. Additional studies showed that only DEX-induced atrophy was accompanied by the induction of thymocyte apoptosis, as detected by multiple nucleosomal length DNA fragments within the first 24 hr. The different kinetics and proportions of subsets in the atrophied thymuses, as well as the distinct patterns of alterations of RAG and TdT expression, and the presence or the absence of apoptosis provide evidence for different mechanisms of thymic atrophy by these agents. The slow induction and longer persistence of thymic atrophy induced by E2 and TCDD, as well as their effects on bone marrow stem cell markers, suggest that bone marrow thymocyte precursors are major targets for these agents.
Silverstone
A E
AE
Department of Microbiology and Immunology, State University of New York, Syracuse 13210.
Frazier
D E
DE
Fiore
N C
NC
Soults
J A
JA
Gasiewicz
T A
TA
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology; D001854:Bone Marrow Cells; D004247:DNA / Q000032:analysis; D003907:Dexamethasone / Q000633:toxicity*; D004958:Estradiol / Q000633:toxicity*; D005260:Female; D005455:Fluorescent Antibody Technique; D016399:Lymphoma, T-Cell / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012313:RNA / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D000072317:Polychlorinated Dibenzodioxins; D004958:Estradiol; D012313:RNA; D003907:Dexamethasone; D004247:DNA