Abstract
Cyclophosphamide (CP) is a complex multifaceted developmental toxicant, with mechanisms of teratogenesis thought to include production of excessive reactive oxygen species (ROS). N-acetyl-L-cysteine (NAC) is a powerful antioxidant that may decrease the toxicity of certain anticancer drugs, such as doxorubicin and CP. The current study explored the potential of NAC to attenuate CP-induced damage to the conceptus. Mated ICR mice were orally dosed with 150 mg/kg/d NAC, 150 mg/kg/d NAC + 20 mg/kg CP, CP only, or vehicle only. CP was administered by intraperitoneal injection on gestation day (GD) 10, and NAC was given by gavage on gestation days 6-13. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. There were significant reductions in the incidences of digit, limb, and tail defects, as well as anasarca and macroglossia, in fetuses exposed to the combination of NAC and CP, compared to fetuses exposed to CP only. NAC did not increase the incidence of any defects when compared to control. Fetuses exposed to NAC weighed significantly more than the average vehicle control fetus. The data indicate that NAC, a well-tolerated, relatively inexpensive antioxidant, appears to reduce the incidence of specific cyclophosphamide-induced malformations when administered prior to, concurrently with, and after exposure to CP.