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The character of reactive metabolites formed from carbamazepine (CBZ) was sought in incubations of [14C]CBZ in hepatic microsomes prepared from adult female mice of a strain (SWV/Fnn) susceptible to CBZ-induced teratogenicity. The formation of radio-labeled protein adducts was used as an index of reactive metabolite exposure. A dependence on cytochrome P450(More)
Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous(More)
The teratogenic effects of valproic acid and its 4-propyl-4-pentenoic acid (4-en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat-induced neural tube defects. In the heat-resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural(More)
Hyperthermia has been known to induce malformations in numerous animal models as well being associated with human abnormalities. This was apparent particularly when the hyperthermia exposure was during the early stages of neural development. Although it was recognized relatively early that these exposures induced cell death, the specific molecular mechanism(More)
Neural tube defects (NTDs) are among the most common congenital malformations, affecting approximately 1 per 1,000 liveborn infants in the United States [Nakano, 1973; Richards et al., 1972]. Maternal exposure to hyperthermia, either through recreational sources or due to an infectious agent, is thought to account for approximately 10% of observed NTD(More)
Although the teratogenicity of valproic acid (VPA) has been well established, the mechanism(s) by which this anticonvulsant drug induces malformations remains controversial. Using the combined molecular techniques of in situ-transcription (IST) and antisense RNA (aRNA) amplification we analyzed VPA-induced alterations in the gene expression for 10 genes(More)
The teratogenic potential of valproic acid has been well established both in experimental models and in human clinical studies. As with all human teratogens, there are genetically determined differences in individual susceptibility to the induction of congenital defects. Using a mouse model of valproate-induced neural tube defects, a study was undertaken to(More)
Neural tube defects (NTDs), although prevalent and easily diagnosed, are etiologically heterogeneous, rendering mechanistic interpretation problematic. To date, there is evidence that mammalian neural tube closure (NTC) initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to a(More)
Removal of senescent erythrocytes (RBC) from the circulation was investigated both in vivo and in vitro using inbred BALB/C mice as a model. Murine RBC were pulse-labeled in situ with 59Fe, and young and old peripheral blood RBC were separated by density gradient centrifugation on Percoll gradients. 59Fe labeled young RBC were found at a density of p 1.09.(More)
Neural tube defects (NTDs) are among the most common of all human congenital defects, with multifactorial etiologies comprising both environmental and genetic components. Several murine model systems have been developed in an effort to elucidate genetic factors regulating expression of NTDs. Strain-dependent differences in susceptibility to teratogenic(More)