This study was designed to determine the effect of caffeine on the teratogenicity of acetazolamide in susceptible and resistant strains of inbred mice. The highly susceptible C57BL/6J and more resistant SWV strain were used. Pregnant C57BL/6J and SWV mice were treated with caffeine, low or high dose acetazolamide, or a combination of both agents during the sensitive period of development. Untreated and vehicle-treated groups served as controls. Individual fetuses were examined for gross morphological abnormalities and skeletal variations.Findings1. A highly significant (P<.001) increase in fetal malformations, especially right forelimb ectrodactyly, was evident in C57BL/6J litters exposed on day 9 of gestation to both agents when contrasted with those exposed to either agent alone. Both frequency and severity of ectrodactyly was potentiated by caffeine.2. The SWV strain was resistant to the interaction of caffeine and acetazolamide when treated on day 9 of gestation. However, a highly significant (P<.001) increase in the rate of fetal malformation was found in litters whose dams were treated with high dose acetazolamide and caffeine on day 8 of gestation. The most common malformations observed were exencephaly and umbilical hernia.3. No differences in maternal mortality, fetal weight, litter size, or embryo mortality could be attributed to treatment in either strain.4. Skeletal examination of the number of ossified cervical and caudal vertebral centra revealed a reduction in ossification among C57BL/6J litters exposed to high dose acetazolamide or acetazolamide plus caffeine. These same centers of ossification were mildly affected by treatment in the SWV strain. In both strains the first cervical vertebrae (Cl) appeared to provide the most sensitive index of teratogenic exposure.ConclusionsThis study provides evidence that a subteratogenic dose of caffeine can potentiate the teratogenic effect of acetazolamide in both C57BL/6J and SWV mice. However, strain associated, and therefore genetically based, differences in sensitivity were confirmed. Skeletal examinations provided evidence that treatment with both agents delayed fetal development in the more susceptible C57BL/6J strain, while reduction of ossification was less evident in the SWV strain. Thus, this parameter also reflects the greater resistance of the SWV strain to the interaction of acetazolamide and caffeine. Finally, these experiments support the idea that chemical interactions may, in part, be responsible for many birth defects of unknown etiology--a claim worthy of further investigation. / Department of Biology

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