Acute studies to investigate the mechanism of action of caffeine as a teratogen in mice.

1 In Charles River CD1 mice, a single dose of 100 mg kg-1 caffeine injected intraperitoneally on day 14 of pregnancy caused a low incidence of cleft palate in the fetuses. 2 Single oral doses of caffeine of 200 and 300 mg kg-1 but not 100 mg kg-1 on day 14, caused cleft palate in some of the fetuses, but was clearly toxic to the dams. 3 Oral doses of caffeine up to 300 mg kg-1 on day 14 of pregnancy did not reduce utero-placental blood flow, placental transfer function, or amniotic fluid volume. 4 An oral dose of 100 mg kg-1 caffeine induced a marked stimulation of adrenocortical secretion producing plasma corticosterone levels of 1248 +/- 129 microgram per 100 ml by 2 h and with elevated levels persisting more than 8 h. 5 It is suggested that the elevated plasma corticosterone is the cause of the cleft palate induced in mice by caffeine. Since corticosterone is a known cleft palate inducer in mice but not in man these results do not predict a hazard from normal caffeine consumption in man.