Dosage time affects alkylating agents induced micronuclei in mouse peripheral blood reticulocytes through the function of erythropoietin
Dosage time affects alkylating agents induced micronuclei in mouse peripheral blood reticulocytes through the function of erythropoietin
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DOI：
10.2131/jts.44.273
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发表时间：
2019-01-01
影响因子：
2
通讯作者：
Shimoi, Kayoko
中科院分区：
文献类型：
--
作者：
Itoh, Keiichi;Masumori, Shoji;Shimoi, Kayoko
先前，我们报道了雄性C3 H/He小鼠腹腔注射乙基亚硝基脲（ENU）（25 mg/kg体重）后，黑暗期（Zeitgeber时间，ZT 15）外周血中微核网织红细胞（MNRET）的频率高于光照期（ZT 3）。在这项研究中，为了阐明这一现象背后的机制，我们研究了使用五种化学品，甲基亚硝基脲（MNU），甲基磺酸乙酯（EMS），丝裂霉素C，环磷酰胺和长春新碱在ZT 3和ZT 15之间观察到的微核（MN）诱导的差异。MNU和EMS，单官能烷基化剂，在ZT 15中显示出比ZT 3处理更高的MNRET频率，类似于ENU。但是，其他化学品未观察到差异。在彗星试验中，在ZT 15中ENU比ZT 3处理诱导更多的DNA损伤。此外，血浆促红细胞生成素（EPO）水平，一个已知的效应MN诱导与Bcl-xL表达介导的抗凋亡活性，是在黑暗中比在光周期。EPO没有增加MNRET的发生率。然而，在ENU治疗组中，在EPO注射后的ZT 3，观察到MNRET的显著增加，与ZT 15治疗相似。与ZT 3相比，在ZT 15用ENU处理的小鼠的骨髓细胞中诱导了更高的凋亡相关基因如Bcl-xL的表达。根据这些结果，推测暴露于单功能烷化剂如ENU的小鼠外周血中MN诱导的差异取决于与骨髓中EPO的昼夜节律相关的凋亡或抗凋亡条件。
Previously, we reported that the frequency of micronucleated reticulocytes (MNRETs) in the peripheral blood of male C3H/He mice intraperitoneally administered ethylnitrosourea (ENU) (25 mg/kg body weight) in the dark period (zeitgeber time, ZT15) was higher than in the light period (ZT3). In this study, to clarify the mechanism underlying this phenomenon, we investigated the differences in micronucleus (MN) induction observed between ZT3 and ZT15 using five chemicals, methylni-trosourea (MNU), ethylmethane sulfonate (EMS), mitomycin C, cyclophosphamide and vincristin. MNU and EMS, monofunctional alkylating agents, showed higher frequencies of MNRETs in the ZT15 than the ZT3 treatment similar to ENU. However, no differences were observed for the other chemicals. In the comet assay, more DNA damage was induced by ENU in the ZT15 than the ZT3 treatment. Furthermore, the plasma erythropoietin (EPO) level, a known effector of MN induction with anti-apoptotic activity mediated by Bcl-xL expression, was higher in the dark than in the light period. EPO did not increase the frequency of MNRETs. However, in the ENU treatment group at ZT3 following EPO injection a significant increase of MNRETs was observed similar to the ZT15 treatment. Higher expression of apoptosis-related genes such as Bcl-xL was induced in bone marrow cells from mice treated with ENU at ZT15 compared with ZT3. From these results, it was speculated that the differences in MN induction in the peripheral blood of mice exposed to monofunctional alkylating agents such as ENU depend on apoptotic or anti-apoptotic conditions related to the circadian rhythms of EPO in bone marrow.