Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells
Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells
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毒死蜱通过 Caspase 3 依赖性基因组不稳定性和拓扑异构酶 II 抑制人胎肝造血干细胞诱导 MLL 易位
DOI：
10.1093/toxsci/kfv153
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发表时间：
2015-10-01
影响因子：
3.8
通讯作者：
Shao, Jing
中科院分区：
文献类型：
--
作者：
Lu, Chengquan;Liu, Xiaohui;Shao, Jing
怀孕期间接触家庭杀虫剂与婴儿白血病风险增加2倍以上有关，毒死蜱是最常用的杀虫剂之一。在早期胎儿发育期间，肝脏是造血器官，其中大部分细胞是CD 34（+）造血干细胞（CD 34（+）HSC）。子宫内对CD 34（+）HSC的损伤已被认为是几种血液疾病发病机制的基础，通常涉及11 q23上的混合系白血病（MLL）基因重排。在这项研究中，我们评估了CPF在人胎肝来源的CD 34（+）HSC中的致白血病潜力。具体而言，暴露于10 μ M CPF导致活力下降，增殖抑制和诱导DNA双链断裂（DSB）和MLL+重排的发生。特别是，我们观察到CPF介导的细胞周期紊乱，如G 0/G1期阻滞所示，与依托泊苷（VP-16）相反，依托泊苷是一种用作阳性对照的抗癌药物，已知可诱导G2/M期阻滞。对DNA双链断裂和MLL+重排机制的进一步研究表明，CPF可能作为拓扑异构酶II毒物，其作用机制与VP-16相似。另一方面，CPF也显示通过活性半胱天冬酶-3激活诱导早期细胞凋亡，这是已知的DNA DSB和MLL+易位的基础途径。我们的数据表明，在子宫内CPF对CD 34（+）HSC的损伤可能会增加婴儿白血病的风险。未来的工作将阐明CPF诱导HSC中MLL+易位的机制和类型。
Household pesticide exposure during pregnancy has been associated with a more than 2-fold increased risk in infant leukemia, and chlorpyrifos (CPF) is among the most frequently applied insecticides. During early fetal development, liver is a hematopoietic organ with majority of cells being CD34(+) hematopoietic stem cells (CD34(+)HSC). The in utero injury to CD34(+)HSC has been known to underlie the pathogenesis of several blood disorders, often involving rearrangements of the mixed-lineage leukemia (MLL) gene on 11q23. In this study, we evaluated the leukemogenic potential of CPF in human fetal liver-derived CD34(+)HSC. Specifically, exposure to 10 mu M CPF led to decrease in viability, inhibition in proliferation and induction of DNA double-strand breaks (DSBs) and occurrence of MLL+ rearrangements. In particular, we observed CPF-mediated cell cycle disturbance as shown by G0/G1 arrest, in contrast to etoposide (VP-16), an anticancer drug used as a positive control and known to induce G2/M arrest. Further study on mechanisms underlying DNA DSBs and MLL+ rearrangements revealed that CPF might act as topoisomerase II poison, a mechanism of action similar to VP-16. On the other hand, CPF was also shown to induce early apoptosis through active caspase-3 activation, a pathway known to underlie DNA DSBs and MLL+ translocations. Our data indicate that in utero injury of CD34(+)HSC by CPF may contribute to the increased risk of infant leukemia. Future work will elucidate the mechanism and the type of CPF-induced MLL+ translocations in HSC.