Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivo

Accumulation of genetic damage in long-lived cell populations with prolifer ative capacity is implicated in tumorigenesis. Hematopoietic stem cells (hs c) maintain lifetime hematopoiesis, and recent studies demonstrate that hsc in leukemic patients are cytogenetically aberrant. We postulated that expo sure to agents associated with increased leukemia risk would induce genomic changes in cells in the hsc compartment. Aneusomy involving chromosomes 2 and 11 in sorted hsc (Lin(-)c-kit(+)Sca-1(+)) and maturing lymphoid and mye loid cells from mice that received topical doses of benzene (bz) or trichlo roethylene (TCE) was quantified using fluorescence in situ hybridization. S ix days after bz or TCE exposure, aneuploid cells in the hsc comport ment i ncrease four- to eightfold in a dose- and schedule-independent manner. Aneu ploid lymphoid and myeloid cells from bz- and TCE-treated mice approximate controls, except after repeated benzene exposures. Aneuploid cells ore more frequent in the hsc compartment than in mature hematopoietic subpopulation s. Hematotoxicity was also quantified in bz- and TCE-exposed hematopoietic subpopulations using two colony-forming assays: CFU-GM (colony-forming unit s/granulocyte-macrophage progenitors) and CAFC (cobblestone area-forming ce lls). Data indicate that bz is transiently cytotoxic (less than or equal to 1 week) to hsc subpopulations, and induces more persistent toxicity (>2 we eks) in maturing, committed progenitor subpopulations. TCE is not hematotox ic at the doses applied. In conclusion, we provide direct evidence for indu ction of aneuploidy in cells in the hsc comportment by topical exposure to bz and TCE. Disruption of genomic integrity and/or toxicity in hse subpopul ations may be one step in leukemic progression. Environ. Mel. Mutagen. 37:1 85-194, 2001. (C) 2001 Wiley-Liss, Inc.