Dieter M P, French J E, Boorman G A, Luster M I
J Leukoc Biol. 1987 Mar;41(3):212-9. doi: 10.1002/jlb.41.3.212.
Compounds with estrogenic activity cause initial toxic responses in the bone marrow characterized by hypocellularity and stem cell myelotoxicity. To elucidate the biochemical nature of these toxic responses, bone marrow cells were collected from mice treated with pharmacological doses of estrogenic chemicals, separated into enriched cell populations, and the enzymatic responses of the individual cell types characterized. Female B6C3F1 mice were injected s.c. with five daily doses of 0.07-5.6 mu moles diethylstilbestrol (DES) or 17-beta estradiol. At 4 days posttreatment body and organ weights were recorded and bone marrow was collected for enumeration and assay of stem cell proliferative responses and enzyme analyses. Treatment with higher dose levels of either estrogenic chemical caused equivalent thymic atrophy, but DES resulted in greater liver and spleen hypertrophy than estradiol. Hexose monophosphate shunt dehydrogenase enzymes in unfractionated bone marrow cells were more sensitive to inhibition by lower estrogen doses than representative enzymes from glycolysis of the Kreb's Cycle, and on an equimolar basis were inhibited to a greater extent by DES than by estradiol. Enzyme analyses after density gradient cell separation indicated that 70-80% of the hexose monophosphate shunt enzyme activity in bone marrow from untreated mice occurred in the enriched band of cells containing predominantly granulocyte-macrophages. The majority of the enzyme inhibition induced by DES treatment could also be ascribed to this cellular population. Furthermore, it was shown that DES had a greater inhibitory effect on the proliferative capacity of the committed stem cells than on the multipotential stem cell population, and the main response was again expressed in the enriched band of cells containing predominantly granulocyte-macrophage precursors. Preliminary endocrine ablation experiments indicated estrogen inhibition of hexose monophosphate shunt enzyme activity was independent of the adrenal and the ovary, but was mediated through the thymus at lower estrogen concentrations.
具有雌激素活性的化合物会在骨髓中引发初始毒性反应，其特征为细胞减少和干细胞骨髓毒性。为阐明这些毒性反应的生化本质，从小鼠身上收集经药理剂量雌激素化学物质处理后的骨髓细胞，将其分离成富集细胞群体，并对各细胞类型的酶反应进行表征。雌性B6C3F1小鼠皮下注射每日五剂，剂量为0.07 - 5.6微摩尔的己烯雌酚（DES）或17-β雌二醇。在处理后第4天，记录体重和器官重量，并收集骨髓用于干细胞增殖反应的计数和测定以及酶分析。用较高剂量水平的任何一种雌激素化学物质处理均导致同等程度的胸腺萎缩，但DES导致的肝脏和脾脏肥大比雌二醇更明显。未分级的骨髓细胞中的磷酸己糖途径脱氢酶比三羧酸循环糖酵解中的代表性酶对较低雌激素剂量的抑制更敏感，且在等摩尔基础上，DES比雌二醇对其抑制程度更大。密度梯度细胞分离后的酶分析表明，未处理小鼠骨髓中70 - 80%的磷酸己糖途径酶活性存在于主要包含粒细胞 - 巨噬细胞的富集细胞带中。DES处理诱导的大部分酶抑制也可归因于该细胞群体。此外，研究表明DES对定向干细胞增殖能力的抑制作用比对多能干细胞群体的抑制作用更大，且主要反应再次在主要包含粒细胞 - 巨噬细胞前体的富集细胞带中表现出来。初步的内分泌切除实验表明，雌激素对磷酸己糖途径酶活性的抑制与肾上腺和卵巢无关，但在较低雌激素浓度下是通过胸腺介导的。
