Induction of serum colony-stimulating activity (CSA) following dimethylnitrosamine (DMN) exposure: effects on...

Dimethylnitrosamine (DMN) exposure in vivo affects hematopoiesis at the level of CFU-GM and CFU-M precursor cells. This effect on hematopoiesis has been shown to be an indirect consequence of DMN exposure; therefore, we examined serum from animals exposed to DMN in vivo for the presence of hematopoietic growth factor activity. Serum obtained from animals exposed to DMN in vivo supported colony formation in normal bone marrow stem cells whereas serum obtained from untreated or vehicle-exposed animals failed to support colony formation. Differential staining of the cells which arose following the in vitro culture of normal bone marrow cells with serum from DMN-exposed animals demonstrated the presence of cells of the monocytic and granulocytic lineages. Pre-treatment of serum from DMN-exposed animals with anti-CSF-1 antibodies prior to in vitro culture had no affect on either cell number, cell phenotype or colony-stimulating activity, suggesting the presence of GM-CSF. Administration of serum from DMN-exposed animals to naive recipient animals resulted in increased percentages of both blood-borne monocytes and neutrophils, mimicking the profile observed in DMN-exposed animals. Studies using oligonucleotide-directed PCR demonstrated the presence of GM-CSF transcripts in the livers obtained following DMN exposure. These results demonstrate the presence of a serum-borne activity(ies) following DMN exposure, most likely GM-CSF, which is capable not only of enhancing macrophage and granulocyte hematopoiesis but also of increasing the numbers of these two cell types in the blood.