Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells.

Household pesticide exposure during pregnancy has been associated with amore than 2-fold increased risk in infant leukemia, and chlorpyrifos (CPF) is among themost frequently applied insecticides. During early fetal development, liver is a hematopoietic organ withmajority 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 CPFmediated 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 onmechanisms underlying DNA DSBs and MLL⁺ rearrangements revealed that CPF might act as topoisomerase II poison, amechanismof 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 CPFmay contribute to the increased risk of infant leukemia. Future work will elucidate themechanismand the type of CPF-induced MLL⁺ translocations in HSC. [ABSTRACT FROM AUTHOR]