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Mutagenesis vol. 8 no. 3 pp. 221-229, 1993
© 1993 UK Environmental Mutagen Society/Oxford University Press

research-article

Induction of micronucleated erythrocytes by recombinant human erythropoietin

Nobuhiro Yajima, Yoshiko Kurata, Tadanori Sawai and Yasuyoshi Takeshita

Research Institute of Life Science, Snow Brand Milk Products Co. Ltd Ishibashi, Shimotsuga-gun, Tochigi 329-05, Japan

Induction of micronucleated erythrocytes by a recombinant human erythropoietin (rhEPO) was examined using both in vitro and in vivo test systems. A small significant and dose-related increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow of mice administered i.p. with 12 500–50 000 IU/kg rhEPO was induced at 48 h sampling time. A clear positive dose-response relationship and significant increase in the frequency of micronucleated reticulocytes (MNRET) in peripheral blood of mice administered i.p. with 400–50 000 IU/kg rhEPO was noted at 48, 72 and 96 h sampling times. Conversely, in bacterial reverse mutation tests, no noticeable increase of auxotrophic revertants was observed in Salmonella typhimurium, TA100, TA98, TA1535, TA1537, or Escherichia coli WP2 uvrA–, by treatment with 188–6000 IU/plate of rhEPO, with or without S9 mix. Furthermore, rhEPO at 750–6000 m/ml did not induce chromosomal aberrations in vitro in CHL cells or human peripheral blood lymphocytes in a direct method nor in a metabolic activation method. Moreover, chromosomal aberrations were not detected in bone marrow cells of CD-1 male mice, even at high rhEPO concentrations (100 000 IU/kg) in vivo. Consequently, it was concluded that errors in the process of enucleation or differentiation of the erythrocytes should be equally considered as possible mechanisms for the increased frequencies of MNPCE and MNRET alongside induction of DNA damage or errors in the process of DNA repair.


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