title: Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells.
abstract: 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 μM 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.
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Chengquan
authors.initials: C
authors.lastname: Lu
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Chunna
authors.initials: C
authors.lastname: Li
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Yachen
authors.initials: Y
authors.lastname: Li
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044;
authors.forename: Shuangyue
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Obstetrics, Maternal and Child Care Service Center of Dalian, Dalian, Liaoning 116033, China;
authors.forename: Shu
authors.initials: S
authors.lastname: Sun
authors.affiliation: Dalian Key Laboratory of Hematology, Department of Hematology of the Second Hospital of Dalian Medical University, Institute of Stem Cell Transplantation of Dalian Medical University, Dalian, Liaoning 116027, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Yan
authors.affiliation: *Dalian Key Laboratory of Hematology, Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University. Dalian, Liaoning, China 116044; jshao@uw.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Shao
mesh_terms: D053148:Caspase 3 / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D043171:Chromosomal Instability / Q000187:drug effects*; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015456:Leukemia, Biphenotypic, Acute / Q000139:chemically induced / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology; D059005:Topoisomerase II Inhibitors / Q000633:toxicity*; D014178:Translocation, Genetic / Q000187:drug effects*
chemical_list: D059005:Topoisomerase II Inhibitors; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D004390:Chlorpyrifos
keywords: DNA double strand break; MLL rearrangement; apoptosis; chlorpyrifos; hematopoietic stem cells; topoisomerase II