Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53-haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC.
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.
Dobrovolsky
Vasily N
VN
US Food and Drug Administration, Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA.
Shaddock
Joseph G
JG
Mittelstaedt
Roberta A
RA
Bishop
Michelle E
ME
Lewis
Sherry M
SM
Lee
Fei W
FW
Aidoo
Anane
A
Leakey
Julian E A
JE
Dunnick
June K
JK
Heflich
Robert H
RH
D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D019259:Lamivudine / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009154:Mutation; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D016159:Tumor Suppressor Protein p53; D019259:Lamivudine; D015215:Zidovudine; D007041:Hypoxanthine Phosphoribosyltransferase