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  • Title: The nitric oxide synthesis inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) causes limb defects in mouse fetuses: protective effect of acute hyperoxia.
    Author: Tiboni GM, Giampietro F, Di Giulio C.
    Journal: Pediatr Res; 2003 Jul; 54(1):69-76. PubMed ID: 12700363.
    Abstract:
    In the present study the relationship between exposure to the nitric oxide synthesis inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with l-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. l-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to l-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of l-NAME-treated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O(2) for 12 h. l-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of l-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of l-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in l-NAME-induced limb defects.
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