INDUCTION OF A REVERSIBLE BLOCK IN MURINE CFU-C DIFFERENTIATION BY EXPOSURE TO NITROUS-OXIDE

Patients subjected to prolonged exposure to nitrous oxide (N2O) often develop megaloblastic bone marrow changes. This toxicity is due to the N2O-mediated inactivation of cobalamin-dependent enzymes with resulta nt perturbations in cell metabolism. The effect of N2O on the behavior of murine colony-forming units-cytokine (CFU-C) in vitro was studied by incubating granulocyte/macrophage colony-stimulating factor (GM-CSF )stimulated bone marrow cultures for 7 days in an atmosphere of either 5% CO2 in air or 50% N2O/5% CO2 in air. Exposure of bone marrow cells in agarose to N2O resulted in an approximately 50% reduction in colon y formation when compared with cultures incubated in air. In contrast, when residual CFU-C numbers were determined in bone marrow liquid cul tures after 7 days of incubation in the presence of GM-CSF, exposure t o N2O was found to dramatically enhance CFU-C recovery. Since these li quid cultures contain a strong differentiation inducer, and are unable to support CFU-C generation, the enhancement of CFU-C recovery in N2O -exposed cultures appears to be related to its ability to induce a rev ersible block in CFU-C differentiation. The reversible block in CFU-C maturation seen in vitro parallels clinical observations where a rapid hematologic recovery is seen in N,O-2-exposed patients treated with h ydroxycobalamin. These observations would suggest that N2O is not mark edly cytotoxic to CFU-C and that its action is, at least in part, cyto static in nature.