retinol-acetate and Abnormalities--Drug-Induced

Topics: Abnormalities, Drug-Induced; Animals; Diterpenes; Dose-Response Relationship, Drug; Gene Expression Profiling; Morphogenesis; Organogenesis; Retinyl Esters; Valproic Acid; Vitamin A

In this study, fetal joint abnormalities caused by cytosine arabinoside, caffeine, sodium salicylate, and retinyl acetate administration during pregnancy, were investigated. In the cytosine-arabinoside-administered group, complete disappearance of joint spaces in the forelimbs, and narrowing or complete disappearance of joint spaces in the hindlimbs was highly noticeable. In the caffeine group, in all forelimb joints starting from art, humeri, there were abnormal fusions in bones, together with occasional disappearance of the joint space. In hindlimbs, similar findings were observed. In the sodium salicylate group, the complete disappearance of joint space and surfaces among humerus-radius and ulna was striking, and occasional fusions in tarsometatarsal joints were also present. Severe narrowing of the same joint space in the retinyl acetate group was striking. Total disappearance of the articulation manus and carpometacarpal joints was observed, together with hindlimb joint and bone findings.

Topics: Abnormalities, Drug-Induced; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antimetabolites, Antineoplastic; Caffeine; Central Nervous System Stimulants; Cytarabine; Diterpenes; Dose-Response Relationship, Drug; Female; Forelimb; Hindlimb; Joints; Male; Mice; Mice, Inbred BALB C; Pregnancy; Prenatal Exposure Delayed Effects; Retinyl Esters; Sodium Salicylate; Vitamin A

Pregnant mice received 10 or 100 mg retinol/kg body wt. by gavage on day 11 of gestation (plug day = day 0). One group of animals was used for a pharmacokinetic study. At various times after dosing, plasma and tissue samples were collected and analyzed by HPLC for retinyl esters, retinol, 13-cis- and all-trans-retinoic acid and 13-cis-4-oxo and all-trans-4-oxoretinoic acid. In the other group the fetuses were removed on day 18 and examined for malformations. After 10 mg/kg retinol, no teratogenic effect was observed. The pharmacokinetic investigation revealed a moderate increase of retinyl esters, retinol and all-trans-retinoic acid in plasma, embryonic tissue, placenta, yolk sac membranes and extraembryonic fluid. A high incidence of severe fetal malformations occurred after 100 mg/kg retinol. These malformations included limb defects (81% of fetuses) and cleft palate (55% of fetuses) which are characteristically found after administration of a single teratogenic dose of an active retinoid on day 11 of gestation. The concentration-time profile of retinoids after 100 mg/kg on day 11 showed a pronounced increase of retinyl esters and retinol in all compartments including the embryo and a massive generation of the polar metabolites all-trans-retinoic acid and all-trans-4-oxoretinoic acid. These polar metabolites were found in the embryo with peak concentrations of 327 +/- 115 and 143 +/- 20.7 ng/g (mean +/- SE) wet tissue, respectively. It is likely that all-trans-retinoic acid and all-trans-4-oxoretinoic acid, both well-known teratogens, largely contributed to the teratogenic outcome. The in-vivo oxidation of retinol may be an important factor in the teratogenic activity of high doses of vitamin A.

Topics: Abnormalities, Drug-Induced; Animals; Chromatography, High Pressure Liquid; Diterpenes; Dose-Response Relationship, Drug; Female; Fetus; Isomerism; Maternal-Fetal Exchange; Mice; Placenta; Pregnancy; Retinyl Esters; Tissue Distribution; Vitamin A; Yolk Sac