Exposure to the Dietary Supplement N-Acetyl-L-Cysteine during Pregnancy Reduces Cyclophosphamide Teratogenesis in ICR Mice.

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.

Exposure to green tea extract alters the incidence of specific cyclophosphamide-induced malformations.

BACKGROUND: Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxygen species. Cyclophosphamide (CP) produces reactive oxidative species, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS: From gestation days (GD) 6-13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 and/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS: Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development.

Developmental toxicity assessment of thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) oligomers in CD-1 mice.

BACKGROUND: Although polymers and hydrogels are used successfully in biomedical applications, including implants and drug delivery devices, smaller molecular weight oligomers, such as those investigated here, have not been extensively studied in vivo. Poly(N-isopropylacrylamide-co-acrylamide), or P(NIPAAm-co-AAm), has a unique thermoresponsive behavior and is under investigation as a novel drug delivery system for metastatic cancer treatment. To date, no studies have been published regarding the safety of P(NIPAAm-co-AAm) to the conceptus. METHODS: From gestation days (GD) 6-16, pregnant CD-1 mice were dosed via i.p. injection with aqueous solutions containing 500, 750, or 1,000 mg/kg/d P(NIPAAm-co-AAm). Dams were sacrificed on GD 17 and their litters were examined for abnormalities. RESULTS: P(NIPAAm-co-AAm) caused no statistically significant difference in maternal weight gain or percent resorbed or dead fetuses compared to control values, but fetal weight was significantly decreased in the two highest dosage groups. CONCLUSIONS: At the highest dosages employed, maternal exposure to P(NIPAAm-co-AAm) was associated with decreased fetal weight. However, as the estimated human exposure levels for persons using this system would be some 1,500-fold lower than the lowest dosage administered in this study, the authors feel that this oligomer was not shown to pose a biologically significant risk at relevant human dosages.