4449

Combined antiretroviral therapy has led to significant reductions in the morbidity and mortality due to mother-to-child transfer of human immunodeficiency virus type 1 infection. In previous studies, we showed that zidovudine (AZT), lamivudine (3TC), and the combination of AZT and 3TC are transplacental mutagens and that the increase in mutants resulting from AZT and the combination of AZT and 3TC is due mainly to large-scale genetic alterations (Environ. Mol. Mutagenesis, in press.). We have now extended our studies by investigating the induction of mutants and micronuclei in mice treated transplacentally and then neonatally. From gestational day (GD) 12 until parturition (typically GD 18), female C57BL/6N and C57BL/6N/Tk mice, which had been mated to male C3H/HeNMTV mice, were treated daily by gavage with AZT (240 mg/kg), 3TC (120 mg/kg), or a combination of AZT and 3TC (240 and 120 mg/kg). Upon birth, the pups were also treated daily on postnatal days (PNDs) 1-8 by gavage with AZT (13.3, 26.6, or 40 mg/kg), 3TC (20 mg/kg), or a combination of AZT and 3TC (13.3 and 6.7, 26.6 and 13.3, or 40 and 20 mg/kg). On PND 9, peripheral blood was obtained from the neonatal B6C3F1 mice to assess the frequency of micronuclei. Three and five weeks following the last treatment, the mutant frequency and types of mutations were determined in the hypoxanthine-guanine phosphoribosyl transferase (Hprt) and thymidine kinase (Tk) genes of splenic T-lymphocytes from the neonatal B6C3F1/Tk mice. AZT and AZT combined with 3TC caused increases in the percentage of reticulocytes, micronucleated reticulocytes, and micronucleated normochromatic erythrocytes, with the extent of micronucleus induction being substantially greater than observed previously in transplacentally-treated mice. Three weeks after the last treatment, AZT and AZT combined with 3TC, but not 3TC by itself, caused a significant increase in the Tk mutant frequency. The increased mutant frequency was associated with loss of heterozygosity (LOH). Five weeks after the last treatment, AZT in combination with 3TC also increased the extent of LOH. None of the treatments increased the Hprt mutant frequency. These data indicate that AZT and AZT combined with 3TC show increased genotoxicity when administered transplacentally and neonatally compared to transplacental treatment alone. (Supported by NTP/NIEHS)

[Proc Amer Assoc Cancer Res, Volume 47, 2006]