Increases in discontinuous rib cartilage and fused carpal bone in rat fetuses exposed to the teratogens, busulfan, acetazolamide, vitamin A, and ketoconazole

Abstract

<jats:p> Skeletal changes induced by treatment of pregnant rats with four potent teratogens, busulfan, acetazolamide, vitamin A palmitate, and ketoconazole, were evaluated using Alizarin Red S and Alcian Blue double-staining to investigate the relationship between drug-induced skeletal malformations and cartilaginous changes in the fetuses. Pregnant rats (N = 8/group) were treated once or twice between gestation days (GDs) 10 to 13 with busulfan at doses of 3, 10, or 30 mg/kg; acetazolamide at 200, 400, or 800 mg/kg; vitamin A palmitate at 100,000, 300,000, or 1,000,000 IU/kg; or ketoconazole at doses of 10, 30, or 100 mg/kg. Uterine evaluations and fetal external and skeletal examinations were conducted on GD 20. Marked skeletal abnormalities in ribs and hand/forelimb bones such as absent/ short/bent ribs, fused rib cartilage, absent/fused forepaw phalanx, and misshapen carpal bones were induced at the mid- and high-doses of busulfan and acetazolamide and at the high-dose of vitamin A palmitate and ketoconazole. Increased incidences of discontinuous rib cartilage (DRC) and fused carpal bone (FCB) were observed from the low- or mid-dose in the busulfan and acetazolamide groups, and incidences of FCB were increased from the mid-dose in the vitamin A palmitate and ketoconazole groups. Therefore, DRC and FCB were detected at lower doses than those at which ribs and hand/forelimb malformations were observed in the four potent teratogens. </jats:p>

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum

“…The sensitive windows for embryonic lethality, cleft palate, digital anomalies, costovertebral fusion and increased incidence of 14th rib were GDs 9‐12, GDs12‐15, GDs 12‐15, GD 14 and GDs 12‐14, respectively. The malformations with sensitive window of GD13 were comparable to our published data except for the detailed skeletal findings related to double staining (Dodo et al ., ). On the other hand, some findings unique to this study and never previously reported in teratology studies with KCZ in rats were obtained, and included costal malformations such as bent, discontinuous and rugged ribs.…”

Effect of Libidibia ferrea bark and seed in maternal reproductive and biochemical outcomes and fetal anomaly in rats

“…Half of the fetuses were fixed in Bouin's fluid, and serial sections followed Wilson's (Wilson, ) visceral examination. Remaining fetuses were prepared for skeletal examination according to the staining procedure described in Dodo et al ().…”

Treatment of common skin infections and infestations during pregnancy

“…Though a case‐control study by Kazy et al. did not find an increased incidence of birth defects in women who had been treated with oral ketoconazole during pregnancy and the drug has been used in the first trimester to treat Cushing's disease, the Food and Drugs Administration (FDA) has classified the oral azoles in category C and there is ample evidence of animal teratogenicity . Interestingly, the incidence of ketoconazole‐induced skeletal defects in rodents can be reduced by coadministration of prednisone, and citral can reduce the incidence of branchial cleft abnormalities induced by azoles .…”