Increases in discontinuous rib cartilage and fused carpal bone in rat fetuses exposed to the teratogens, busulfan, acetazolamide, vitamin A, and ketoconazole.
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.
Dodo
T
T
Planning & Coordination Department, Biopharmaceutical Assessments Core Function Unit, Eisai Co., Tokodai Tsukuba-shi, Ibaraki, Japan. t-dodo@hhc.eisai.co.jp
Uchida
K
K
Hirose
T
T
Fukuta
T
T
Kojima
C
C
Shiraishi
I
I
Kato
E
E
Horiba
T
T
Mineshima
H
H
Okuda
Y
Y
Maeda
M
M
Katsutani
N
N
Hirano
K
K
Aoki
T
T
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000086:Acetazolamide / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D002066:Busulfan / Q000008:administration & dosage / Q000633:toxicity; D002348:Carpal Bones / Q000002:abnormalities*; D002356:Cartilage / Q000002:abnormalities*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D047109:Fetal Development / Q000187:drug effects; D005327:Fetal Resorption / Q000139:chemically induced; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000002:abnormalities; D007654:Ketoconazole / Q000008:administration & dosage / Q000633:toxicity; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D000084562:Retinyl Esters; D012272:Ribs / Q000002:abnormalities*; D013723:Teratogens / Q000633:toxicity*; D014801:Vitamin A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity
D004224:Diterpenes; D000084562:Retinyl Esters; D013723:Teratogens; D014801:Vitamin A; C014794:retinol palmitate; D002066:Busulfan; D000086:Acetazolamide; D007654:Ketoconazole