Research Article

Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53-haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC†‡

  1. Vasily N. Dobrovolsky1,*,
  2. Joseph G. Shaddock1,
  3. Roberta A. Mittelstaedt1,
  4. Michelle E. Bishop1,
  5. Sherry M. Lewis2,
  6. Fei W. Lee2,
  7. Anane Aidoo1,
  8. Julian E.A. Leakey2,
  9. June K. Dunnick3,
  10. Robert H. Heflich1

Article first published online: 14 MAR 2007

DOI: 10.1002/em.20280

Issue

Environmental and Molecular Mutagenesis

Environmental and Molecular Mutagenesis

Volume 48, Issue 3-4, pages 270–282, April - May 2007

Additional Information

How to Cite

Dobrovolsky, V. N., Shaddock, J. G., Mittelstaedt, R. A., Bishop, M. E., Lewis, S. M., Lee, F. W., Aidoo, A., Leakey, J. E.A., Dunnick, J. K. and Heflich, R. H. (2007), Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53-haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC. Environ. Mol. Mutagen., 48: 270–282. doi: 10.1002/em.20280

Author Information

  1. 1

    US Food and Drug Administration, Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, Arkansas

  2. 2

    Office of Scientific Coordination, National Center for Toxicological Research, Jefferson, Arkansas

  3. 3

    National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina

*3900 NCTR Rd., HFT-120, Jefferson, AR 72079, USA

  1. †

    This article is a US Government work and, as such, is in the public domain in the United States of America.

  2. ‡

    Invited article on the genotoxicity of perinatal NRTI therapy.

Publication History

  1. Issue published online: 19 MAR 2007
  2. Article first published online: 14 MAR 2007

Funded by

  • National Center for Toxicological Research (Food and Drug Administration);
  • National Institute for Environmental Health Sciences (National Toxicology Program)

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Keywords:

  • nucleoside analog reverse transcriptase inhibitors;
  • reticulocytes;
  • normochromatic erythrocytes;
  • transplacental exposure;
  • neonatal exposure

Abstract

Azidothymidine (AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) that is used for reducing mother-to-child transmission of human immunodeficiency virus I. Combinations of AZT and 3′-thiacytidine (3TC) are even more effective than AZT alone. AZT, however, is a mutagen and carcinogen in rodent models and 3TC can increase the genotoxicity of AZT. Since p53 plays a key role in human and mouse tumorigenesis, p53-haplodeficient mice are currently being evaluated as a model for assessing the carcinogenicity of perinatal exposure to NRTIs. In the present study, male C57BL/6 p53+/+ and p53−/− mice were mated with C3H p53+/+ females; the pregnant females were treated on gestation day 12 through parturition with 40, 80, and 160 mg/kg of AZT or a combination of 160 mg/kg AZT and 100 mg/kg 3TC (AZT-3TC); the p53+/+ and p53+/− offspring were treated daily after birth through postnatal day (PND) 28. The frequencies of micronucleated reticulocytes (MN-RETs) and micronucleated normochromatic erythrocytes (MN-NCEs) were determined on PND1, PND10, and PND28; the frequency of Hprt mutant lymphocytes was measured on PND28. The frequencies of MN-RETs and MN-NCEs were increased in treated animals at all time points; there were no differences in the responses of p53+/+ and p53+/− animals treated with identical doses of NRTIs. After correction for clonal expansion, both AZT and AZT-3TC treatments induced small but significant increases in the frequency of Hprt mutant lymphocytes in p53+/− mice, but not in p53+/+ mice. The data indicate that p53 haplodeficiency affects the genotoxicity of NRTIs; thus, p53+/− mice may be a sensitive model for evaluating the carcinogenicity of perinatal exposure to NRTIs. Environ. Mol. Mutagen., 2007. Published 2007 Wiley-Liss, Inc.

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