Prevention of caffeine-induced limb malformations by maternal adrenalectomy

Caffeine at high doses is a known rodent teratogen and induces limb malformations along with cleft palate in various strains of rats and mice. Fujii and Nishimura ('74) postulated that caffeine was teratogenic by virtue of catecholamine release from maternal or embryonic tissue. We tested this hypothesis by surgically removing the maternal adrenal gland on day 6 of pregnancy and then administering 175 mg/kg of caffeine intraperitoneally at 1600 h day 11 and 900 h day 12. The teratogenic effects of caffeine in adrenalectomized versus nonadrenalectomized AKR mice were assessed in day 18 fetuses. Thirty percent of the surviving offspring were malformed in caffeine-treated, nonadrenalectomized dams compared to 7% of the offspring from adrenalectomized dams. Therefore we believe caffeine teratogenesis is initiated by release of catecholamines from the maternal adrenal gland.