Developmental Toxicity of Oral Administered Low- and High-Dose of Folate Antagonist, Methotrexate in Female CD-1 Mice

Objective: The present study was carried out to evaluate potential adverse effects of the low and high doses of MTX through implantation and organogenesis. Materials and Methods: Pregnant female mice were given doses of 0, 0.13 and 0.42 mg/kg bw/week methotrexate orally on gestation day zero through day 15 along with vehicle-treated control. Status of gravid/non-gravid uterus, the number of corpora lutea in the ovary, implantation status, fetal resorption, fetal body weight, and external, visceral and skeletal malformations were recorded. Results: Maternal toxicity, as evidenced by reduction in body weight gain and signs of toxicity was observed at the low- and high-dose groups. Developmental toxicity that included significantly reduction in the number of live fetuses, mean fetal weight and increased resorption sites was observed only in the treated group of 0.42 mg/ kg bw/week. Also, there was significant increase in the incidence of fetuses with external, skeletal or visceral malformations in 0.42 mg/ kg bw/week dose group. It seems likely that marked maternal toxicity contributed to the observed fetotoxicity. Also, these results reveal that the malformations by MTX treatment are correlated to the disrupted circulating levels of reproductive hormones and histoarchitecture of ovary. Conclusion: The results suggest that the MTX had developmental toxicity and teratogenicity at high dose level, which could affect pregnancy, implantation and gestation. The no-observed-effect level (NOAEL) in the present study for developmental toxicity was 0.13 mg/ kg bw/week.