Silverstone A E, Frazier D E, Fiore N C, Soults J A, Gasiewicz T A
Department of Microbiology and Immunology, State University of New York, Syracuse 13210.
Toxicol Appl Pharmacol. 1994 Jun;126(2):248-59. doi: 10.1006/taap.1994.1114.
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.
研究了单剂量地塞米松（DEX）、β-雌二醇-17-戊酸酯（E2）和2,3,7,8-四氯二苯并对二恶英（TCDD）对胸腺萎缩动力学以及相关骨髓和胸腺细胞表型改变的影响。结果表明这些化合物的作用机制存在差异。在这三种化合物中，DEX在3天时诱导最大程度的萎缩，并在第12天完全恢复。在最大萎缩点，RAG-1+TdT+CD4+8+3int胸腺细胞群体按比例减少最多。相比之下，TCDD和E2在第12天时导致最大程度的胸腺萎缩。E2治疗与DEX一样，导致RAG-1+TdT+CD4+8+3int群体优先减少，但与DEX不同的是，这种减少持续存在。TCDD诱导的胸腺萎缩是由于所有类型胸腺细胞按比例减少。TCDD在胸腺中并未使TdT+RAG-1+细胞相对显著减少。TCDD和E2均使骨髓中的TdT和RAG-1缓慢且持续减少，这与DEX处理动物骨髓中这些标志物的快速减少和快速恢复形成对比。额外的研究表明，只有DEX诱导的萎缩伴随着胸腺细胞凋亡的诱导，这在前24小时内通过多个核小体长度的DNA片段检测到。萎缩胸腺中不同亚群的动力学和比例差异，以及RAG和TdT表达的不同改变模式，以及凋亡的存在与否，为这些药物导致胸腺萎缩的不同机制提供了证据。E2和TCDD诱导的胸腺萎缩的缓慢诱导和较长持续时间，以及它们对骨髓干细胞标志物的影响，表明骨髓胸腺细胞前体是这些药物的主要靶点。
