Melissa M. Bailey

Developmental toxicity assessment of the ionic liquid 1-butyl-3-methylimidazolium chloride in CD-1 mice

The effects of prenatal exposure of mice to the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) were studied because of the potential for human exposure as a result of water or soil contamination from industrial effluent or accidental spills. After exposure to the IL, fetal weight was significantly decreased at the two highest dosages (P≤ 0.01). Malformations were also somewhat more numerous at the highest dosage, suggesting that [C4mim]Cl may be teratogenic, although the apparent increase was not statistically significant. Maternal toxicity was also present, as shown by a dose-dependent increase in maternal morbidity and mortality during the course of treatment. Therefore from these results, [C4mim]Cl appears to be developmentally toxic at maternally toxic dosages, although the mechanism is unknown.

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.

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.

Investigations into Concurrent Exposure to Green Tea Extract and Phenytoin on the Incidence of Cleft Palate in CD-1 Mice

Phenytoin (PHT) is an efficacious anticonvulsant agent that is commonly used in the treatment of epileptic seizures. However, the use of phenytoin during pregnancy is associated with a group of birth defects known as Fetal Hydantoin Syndrome (FHS), which include cleft palate and retarded growth. Phenytoin may cause its adverse effects through the production of reactive oxygen species (ROS). Green tea extract (GTE) contains epigallocatechin-3-gallate (EGCG), which exhibits free radical scavenging activity and may attenuate the effects of ROS. The purpose of this study was to investigate the potential of administration of GTE to attenuate teratogenic effects induced by phenytoin. Phenytoin sodium salt (in DI water adjusted to pH 11) was administered via gavage on gestation days (GD) 12 and 13, and its controls were dosed with pH-adjusted water on GD 12 and 13. GTE or DI water was administered from GD 8–16 to mated CD-1 mice. Controls received both vehicles (DI water and pH-adjusted water). Mated females were assigned to one of the following treatment groups: 400 mg/kg/d GTE only, 85 mg/kg/d PHT only, 200 mg/ kg/d GTE + 85 mg/kg/d PHT, or 400 mg/kg/d GTE + 85 mg/kg/d PHT. Fetuses were removed on GD 17, weighed, measured, and examined for malformations. Fetuses exposed to PHT alone showed a significant increase in the incidence of cleft palate (p ≤ 0.05) The incidence of cleft palate was lower in fetuses exposed to 200 or 400 mg/kg/d GTE, compared to fetuses exposed to PHT alone; however, the reduction was not statistically significant. Fetal weight, maternal weight gain, and the incidence of fetal resorptions did not differ significantly among treatment groups. Prior and concurrent exposure to GTE may have reduced the incidence of cleft palate in fetuses exposed to PHT, but any reduction appears to have been modest under the current experimental conditions.