Murine Teratology of Fluconazole: Evaluation of Developmental Phase Specificity and Dose Dependence

Abstract

The potential of in utero exposure to fluconazole to initiate teratogenesis was analyzed in ICR (CD-1) mice. Developmental phase specificity was determined by treating mice with single oral doses of 700 mg/kg on gestational day 8, 9, 10, 11, or 12. Control animals received vehicle on gestational days 8-12. Gestational day 10 was identified as the phase of maximal sensitivity for induction of cleft palate, the predominant teratogenic effect induced by fluconazole, with 50% of fetuses exposed on this developmental phase being affected. After treatments on gestational day 8, 9, 11, or 12, cleft palate occurred with lower frequencies: 12, 21, 28.7, and 2.7%, respectively. Examination of skeletal morphology revealed anomalies of the middle ear apparatus in 15% of the fetuses that were exposed on gestational day 8. Dysmorphic tympanic ring and absence of the incus were the more common ear anomalies recorded. Reduced humeral length was noted in 22% of fetuses that were exposed on gestational day 10. Dose-response relationship was investigated by treating animals with 0 (vehicle), 87.5, 175, or 350 mg/kg on gestational day 10, coincident with the phase of peak teratogenic sensitivity. Besides showing that fluconazole operates under a strict dose-response mechanism, the study identified 175 mg/kg as the lowest observed adverse effect level for cleft palate induction, with 7.6% of the exposed fetuses being affected.