Oxidative DNA damage in fetal tissues after transplacental exposure to 3 '-azido-3 '-deoxythymidine (AZT)

The nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) has been used succ essfully to reduce the incidence of transplacental and perinatal transmissi on of the HIV virus. However, prolonged treatment with high doses of AZT is utilized in this therapy, and AZT has been found to be a perinatal carcino gen in mice, Any possible perinatal carcinogenic side effects in the human can best be managed if the mechanism is understood. AZT targets mitochondri a and might cause increased intracellular production of reactive oxygen spe cies (ROS), We tested whether transplacental AZT may cause oxidative damage in nuclear DNA of fetal tissues. CD-1 Swiss pregnant mice were treated wit h the transplacental carcinogenesis regimen (25 mg/day AZT, for gestation d ays 12-18) and tissues collected on the day of birth. Significant increases in 8-oxo-2'-deoxyguanosine (8-oxo-dG) were found in the livers, a target t issue for transplacental carcinogenesis, and in the kidneys. A nonsignifica nt increase occurred in brain, with no change in lung. Tissues were also ob tained from fetal patas monkeys (Erythrocebus patas), whose mothers had rec eived 10 mg AZT/day during the last half of gestation. Although limited num bers of samples were available, possible increases in 8-oxo-dG were noted, relative to controls, for placenta and for fetal lung and brain (P = 0.055 for treatment-related increases in these tissues). These results suggest th at an increase in reactive oxygen species could contribute to the mechanism of transplacental carcinogenesis by AZT in mice, and that this may also oc cur in primates.