Hematopoietic neoplastic diseases develop in C3H/He and C57BL/6 mice after benzene exposure: Strain differences in bone marrow tissue responses observed using microarrays
Hematopoietic neoplastic diseases develop in C3H/He and C57BL/6 mice after benzene exposure: Strain differences in bone marrow tissue responses observed using microarrays
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DOI：
10.1016/j.cbi.2009.12.005
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发表时间：
2010-03-19
影响因子：
5.1
通讯作者：
Hirabayashi, Yoko
中科院分区：
文献类型：
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作者：
Inoue, Tohru;Hirabayashi, Yoko
在本研究中，C57BL/6和C3H/He品系的TrP53基因缺陷和野生型小鼠暴露于苯(33、100和300ppm；每天6小时，每周5天，持续26周)，然后进行终身观察。结果表明，C57BL/6小鼠的非胸腺淋巴瘤和C3H/He小鼠的急性髓系白血病(AML)的发病率在TrP53基因缺陷小鼠的低暴露水平下呈线性反应，C57BL/6小鼠的胸腺淋巴瘤和C3H/He小鼠的非胸腺淋巴瘤的发病率增加，没有平台式的上限；因此，前者在低剂量苯暴露的情况下可疑地诱导造血肿瘤(HPN)是基于野生型小鼠的DNA修复潜力，而后者在高剂量苯暴露的情况下HPNS的有限增加被认为是由于野生型小鼠的过度凋亡所致。在急性髓系白血病的发生率方面，虽然300ppm的苯雾化吸入可诱导9%的野生型C3H/He小鼠发生急性髓细胞白血病，但在TrP53基因缺陷的C3H/He小鼠中诱发38%的急性淋巴细胞白血病。由于在Trp53基因缺陷的小鼠中也观察到了AML，包括在C57BL/6小鼠中，苯暴露也可能是不同品系小鼠的AML的有效诱因。在本研究中，为了阐明造血干细胞特异性的芳香烃受体相关的低剂量不良反应，本研究分析了150 mg/kg bw间歇暴露2周后28天骨髓中整体基因的表达。苯，通过灌胃，即相当于上述300ppm的吸入方案。我们观察到两种概念上不同的基因表达谱；每组小鼠共有的“共同基因谱”(CGPS)和“随机基因谱”(SGPS)，即从一只小鼠到另一只小鼠的独特联合基因。分别测定各实验组小鼠的CGPS和每只小鼠的SGPS。在CGPS方面，C3H/He和C57BL/6小鼠在基因表达谱上存在互易的差异，这两种基因都可能与白血病的发生有关；即在C3H/He小鼠中，SLtm和Cryl1分别与抑制细胞凋亡和基因组不稳定有关，而在C57BL/6小鼠中，与DNA修复减少和基因组不稳定相关的ATRX/rad54和Kdm2a分别以下调为主。这些发现表明，苯暴露引起的这些基因表达的相互差异可能导致每个菌株经历不同的造血肿瘤途径。相比之下，每个单独的鼠标通常显示一个唯一的SGP。SGP通常包括转录因子，这些转录因子调节相互的信号通路，包括进一步的SGP。其中，凋亡相关基因在C57BL/6小鼠和C3H/He小鼠中的表达归因于不同的SGP组合。这种随机的逐个病例的基因表达可能与苯暴露后观察到的个体和菌株差异很好地一致。由于基因芯片微阵列技术可以阐明基因表达谱中的随机变化，因此讨论了可能的随机毒理学及其未来的作用。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
In this study, Trp53-deficient and wild-type mice of both C57BL/6 and C3H/He strains were exposed to benzene (33, 100, and 300 ppm; 6 h/day, 5 days/week for 26 weeks) and then observed for lifetime. As results, first, the incidence of nonthymic lymphomas in C57BL/6 mice and acute myeloid leukemias (AMLs) in C3H/He mice showed linear responses at the lower exposure level in Trp53-deficient mice; second, the incidence of thymic lymphomas in C57BL/6 mice and nonthymic lymphomas in C3H/He mice increased without a plateau-like ceiling; thus, the former equivocal induction of hematopoietic neoplasms (HPNs) in the case of low-dose benzene exposure was assumed to be based on the DNA repair potential in wild-type mice, and the latter limited increase in HPNs in the case of high-dose benzene exposure was considered to be due to excessive apoptosis in wild-type mice. Concerning the incidence of AMLs, though a dose of 300 ppm benzene inhalation induced 9% AMLs in wild-type C3H/He mice-AML-prone, it induced AMLs in 38% of Trp53-deficient C3H/He mice. Because AMLs were also observed in Trp53-deficient mice, including in the C57BL/6 mice, benzene exposure may also be a potent inducer of AMLs in mice with some strain differences. In the present study, to elucidate the hematopoietic stem cell-specific, aryl hydrocarbon-receptor-related low-dose adverse effect, global gene expression in the bone marrow was analyzed at 28 days after 2-week-intermittent exposure to 150 mg/kg b.w. benzene, by gavage, i.e., equivalent to the above inhalation protocol with 300 ppm. We observed two conceptually different gene expression profiles; "common gene profiles" (CGPs) shared among mice in each group, and "stochastic gene profiles" (SGPs), i.e., unique union genes from one individual mouse to another. The CGPs of the experimental group and the SGPs of each individual mouse were separately characterized by individual assay. Concerning the CGPs, reciprocal strain differences between C3H/He and C57BL/6 mice in expression gene profiles, both plausible for leukemogenesis, were identified; namely, dominant downmodulations of Sltm and Cryl1, related to suppression of apoptosis and genomic instability in C3H/He mice, respectively, and dominant downmodulations of Atrx/rad54 and Kdm2a, related to a decrease in DNA repair and genomic instability, respectively, in C57BL/6 mice. These findings imply that these reciprocal gene expression differences induced by benzene exposure may lead each strain to undergo different hematopoietic neoplastic pathways. In contrast, each individual mouse often shows a unique SGP. SGPs often include transcription factors, which regulate reciprocal signaling pathways including further SGPs. Among them, apoptosis-related genes expressed in C57BL/6 mice and those in C3H/He mice were attributable to different combinations of SGPs. Such stochastic case-by-case gene expression may be in good agreement with the individual and strain differences observed following benzene exposure. Because gene chip microarray techniques can elucidate stochastic changes in gene expression profiles, possible stochastic toxicology and its future role are discussed. (C) 2009 Elsevier Ireland Ltd. All rights reserved.