Persistence of aneuploid immature/primitive hemopoietic sub-populations inmice 8 months after benzene exposure in vivo

Benzene (bz) is a common environmental contaminant associated with increase d risk of myeloid leukemia. Chronic bz exposure in vivo increases the frequ ency of aneuploid circulating lymphocytes in humans. However, there is no i nformation about persistence of bz-associated aneuploidy in immature/primit ive cells, at risk of leukemic transformation, after bz exposure in vivo. W e explored the relationship between the induction and persistence of aneupl oidy in primitive hemopoietic cells from mice that received oral doses of b z in vivo. Short- and long-term persistence of aneuploidy were evaluated in immature/primitive sub-populations (Lin(-)c-kit(+)Sca-1(+)), as well as ly mphoid and myeloid cells, 6 days and 2-8 months after exposure. Mice receiv ing bz in a corn oil carrier, or corn oil alone, both have increased aneupl oidy frequencies (1-5%, compared to <1% in untreated controls) in all sub-p opulations. 6 days after exposure. However, unlike bz-induced aneuploidy, c orn oil-induced aneusomies are transient, with frequencies returning to bac kground levels in lymphoid and myeloid cells, 9 weeks after exposure. The f requency (5-9%) of aneuploid lymphocytes and myeloid cells is higher at 9 w eeks than at 6 days, suggesting that bz disrupts chromosomal segregation in differentiated cells and/or progenitors. About 8 months after bz exposure, the Lin(-)c-kit(+)Sca-1(+) sub-population contains up to 14% aneuploid cel ls with numerical chromosomal aberrations affecting chromosomes 2 or 11. Th ese data demonstrate that bz induces DNA copy number changes in immature/pr imitive cells, and that these changes persist for long periods. Although, i nitial exposures are not leukemogenic, subsequent exposures of cells to gen otoxins or oxidative radicals that induce additional genetic hits may incre ase the risk of transformation. The contribution of bz-induced aneuploidy i n immature/primitive cells to leukemogenesis remains to be determined. (C) 2001 Published by Elsevier Science B.V.