Fetal anticonvulsant syndrome in rats: dose- and period-response relationships of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure on the structural and functional development of the offspring.
Three experiments were performed in order to develop a murine model of the postnatal functional defects recently described in humans as the fetal anticonvulsant syndromes. In the first experiment, the lower end of the malformation dose-response curves for diphenylhydantoin (DPH), trimethadione (TMD) and phenobarbital (PB) were established. Using this information, doses of each drug were selected for the postnatal behavioral teratology experiments that did not significantly increase the malformation rate. In experiment 2, all three drugs produced some evidence of postnatal dysfunction at the highest nonmalforming doses tested (DPH at 200, TMD at 250 and PB at 80 mg/kg, administered on days 7-18 of gestation). No effects were seen at substantially lower doses. DPH produced reduced maternal and offspring weight gain and increased offspring mortality. DPH also produced increased pivoting locomotion, delayed auditory startle and swimming development, increased adult ambulation along with decreased rearing, increased water maze errors and increased rotational behavior. TMD produced a small increase in offspring mortality, but no effects on maternal or offspring weight. TMD also produced increased adult ambulation, reduced spontaneous alternation frequency and increased water maze errors. PB increased offspring mortality, but did not affect maternal or offspring weight. PB also delayed one aspect of swimming development, and showed suggestive trends toward delayed startle and reduced alternation behavior. In experiment 3, the highest dose of each drug was administered at one of three discrete periods during gestation, days 7 to 10, 11 to 14 or 15 to 18. DPH increased pivoting and delayed swimming in those exposed on days 11 to 14 or 15 to 18 of gestation. For the 11 to 14-day exposure group, DPH also increased figure 8 ambulation and water maze errors and impaired passive avoidance retention. TMD increased offspring mortality in those exposed on days 11 to 14 and 15 to 18, delayed swimming in those exposed on days 7 to 10 and impaired water maze performance in those exposed on days 15 to 18. PB increased offspring mortality in all exposure groups, but impaired growth only in those exposed on days 11 to 14. PB also delayed swimming in those exposed on days 7 to 10 and 11 to 14. DPH produced virtually the same pattern of effects in experiment 3 as in experiment 2, but the effects were less severe with the shorter exposures used in experiment 3. The effects were most pronounced during midorganogenesis (days 11-14) with fewer effects later (days 15-18) and the fewest effects earlier (days 7-10). Overall, the present data are consistent with clinical findings regarding the fetal hydantoin, TMD and barbital syndromes.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002658:Developmental Disabilities / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D010080:Oxazoles / Q000633:toxicity*; D010634:Phenobarbital / Q000633:toxicity*; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013216:Reflex, Startle / Q000187:drug effects; D013550:Swimming; D013577:Syndrome; D013997:Time Factors; D014293:Trimethadione / Q000633:toxicity*
D010080:Oxazoles; D010672:Phenytoin; D014293:Trimethadione; D010634:Phenobarbital