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

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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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