Interactions in developmental toxicology: Combined action of restraint stress, caffeine, and aspirin in pregnant mice

Background: Stress can result in an increased use of substances such as caf feine and aspirin. The effect of maternal stress on concurrent exposure to caffeine and aspirin on prenatal development was assessed in mice. Methods: On gestational day 9, mice were assigned to three treatment groups orally exposed to caffeine (30 mg/kg), aspirin (250 mg/kg), or a combinati on of caffeine (30 mg/kg) and aspirin (250 mg/kg). Three additional groups of pregnant animals received similar caffeine and aspirin doses and were im mediately subjected to restraint for 14 hr. Control groups included unrestr ained and restrained pregnant mice not exposed to caffeine or aspirin. All dams were euthanized on gestational day 18. Live fetuses were evaluated for sex, body weight, and external, internal, and skeletal malformations and v ariations. Results: A single oral dose of caffeine or aspirin did not cause significan t maternal toxicity. However, coadministration of these drugs with restrain t produced some adverse maternal effects (i.e., reduction in maternal weigh t gain and food consumption on gestational days 9-11). In relation to embry o/fetal toxicity, the incidence of some skeletal defects was significantly increased after exposure to caffeine, aspirin, or maternal restraint, and t heir binary and ternary combinations. Conclusions: Although caffeine and aspirin were given in a single dose in t his study, the results suggest that prenatal stress could slightly exacerba te the maternal and developmental toxicity of the combination of these drug s in mice.