Lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol) synergistically induce apoptosis in murine lymphoid organs.
Lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol) synergistically induce apoptosis in murine lymphoid organs.
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DOI：
10.1093/toxsci/53.2.253
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发表时间：
2000-02
期刊：
影响因子：
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通讯作者：
H. R. Zhou;J. Harkema;J. Hotchkiss;D. Yan;R. Roth;J. Pestka
中科院分区：
文献类型：
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作者：
H. R. Zhou;J. Harkema;J. Hotchkiss;D. Yan;R. Roth;J. Pestka
人体暴露于革兰氏阴性细菌脂多糖（LPS）是常见的，可能对化学毒性有重要影响。LPS先前已被证明可以协同增强霉菌毒素的毒性。由于这两种毒素在高剂量下单独靶向淋巴器官，因此我们评估了分别通过腹腔注射和灌胃分别暴露于亚阈剂量鼠伤寒沙门菌LPS和呕吐毒素（VT）的B6C3F1小鼠在暴露12小时后对淋巴组织凋亡的影响。凝胶电泳结果显示，LPS （0.5 mg/kg体重）和VT （25 mg/kg体重）协同作用可导致胸腺、脾脏和Peyer’s斑块细胞凋亡。在对组织切片进行末端脱氧核苷酸转移酶（TdT）介导的荧光素- dutp缺口末端标记（TUNEL）后，与单独给药相比，在共暴露动物的胸腺、脾脏、Peyer’s patches和骨髓中观察到荧光强度的显著增强，表明细胞凋亡。苏木精染色和伊红染色的组织切片显示了淋巴细胞凋亡的特征，包括核染色质的明显凝聚、细胞核的断裂和细胞凋亡小体的形成。与单独给药相比，VT （25 mg/kg体重）和LPS （0.5 mg/kg体重）联合给药显著增加了小鼠胸腺和脾脏的凋亡组织数量（p<0.05）。流式细胞术结合碘化丙啶染色检测胸腺、脾脏、Peyer’s patches和骨髓细胞悬液的凋亡，与单独给药LPS和VT相比，共给药组的凋亡细胞百分比显著增加（p<0.05）。这些结果为LPS暴露显著增强毛霉烯的毒性以及免疫系统是这些相互作用的主要目标的假设提供了定性和定量证据。
Human exposure to Gram-negative bacterial lipopolysaccharide (LPS) is common and may have an important influence on chemical toxicity. LPS has been shown previously to enhance synergistically the toxicity of trichothecene mycotoxins. Because either of these toxin groups alone characteristically target lymphoid organs at high doses, we evaluated the effects of coexposure to subthreshold doses of Salmonella typhimurium LPS and vomitoxin (VT) administered by intraperitoneal injection and oral gavage of B6C3F1 mice, respectively, on apoptosis in lymphoid tissues after 12-h exposure. The capacity of LPS (0.5 mg/kg body weight) and VT (25 mg/kg body weight) to act synergistically in causing apoptosis in thymus, spleen, and Peyer's patches was suggested by increased internucleosomal DNA fragmentation in whole cell lysates as determined by gel electrophoresis. Following terminal deoxynucleotidyl transferase (TdT)-mediated fluorescein-dUTP nick end-labeling (TUNEL) of tissue sections, a dramatic enhancement of fluorescence intensity indicative of apoptosis was observed in thymus, spleen, Peyer's patches, and bone marrow from coexposed animals as compared to those given the agents alone. Evaluation of hematoxylin and eosin-stained tissue sections of treatment mice revealed the characteristic features of lymphocyte apoptosis, including marked condensation of nuclear chromatin, fragmentation of nuclei, and formation of apoptotic bodies in tissues from mice. Combined treatment with VT (25 mg/kg body weight) and LPS (0.5 mg/kg body weight) significantly increased (p<0.05) the amount of apoptotic thymic and splenic tissue as compared to the expected additive responses of mice receiving either toxin alone. When apoptosis was examined in cell suspensions of thymus, spleen, Peyer's patches, and bone marrow by flow cytometry in conjunction with propidium iodide staining, the percentage of apoptotic cells was significantly increased (p<0.05) in cotreatment groups as compared to the additive responses to LPS and VT given alone. The results provide qualitative and quantitative evidence for the hypothesis that LPS exposure markedly amplifies the toxicity of trichothecenes and that the immune system is a primary target for these interactive effects.