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Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53‐haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC
Author(s) -
Dobrovolsky Vasily N.,
Shaddock Joseph G.,
Mittelstaedt Roberta A.,
Bishop Michelle E.,
Lewis Sherry M.,
Lee Fei W.,
Aidoo Anane,
Leakey Julian E.A.,
Dunnick June K.,
Heflich Robert H.
Publication year - 2007
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20280
Subject(s) - hypoxanthine guanine phosphoribosyltransferase , mutant , clastogen , biology , mutagen , micronucleus test , toxicology , microbiology and biotechnology , chemistry , genetics , toxicity , dna , gene , organic chemistry
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.