Evaluation of effects of exposure to n-acetyl-l-cysteine on cyclophosphamide teratogenesis in CD-1 mice

Abstract

Reactive oxygen species (ROS) are necessary for normal development; however, ROS may cause damage to a developing fetus if present in excessive amounts, as can be the case in maternal drug use or maternal disease states. Cyclophosphamide (CP) is a complex multifaceted teratogen with mechanisms of teratogenesis thought to include production of excessive ROS. N-acetyl-L-cysteine (NAC) is a powerful antioxidant that offers protection from the toxicity of certain anticancer drugs, like doxorubicin and CP. No studies have explored the potential of NAC to attenuate CP-induced damage to the conceptus. The current study explored the effect of concurrent exposure to NAC and CP. Mated CD-1 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 (GD) 6-13. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. There was a significant reduction in the incidence 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, on average, weighed slightly, though not significantly, more than the average control fetus. The data indicate that NAC is a well-tolerated, relatively inexpensive antioxidant that appears to reduce the incidence of specific cyclophosphamide-induced malformations when administered prior to, concurrently and after exposure to CP.