© 1984 Oxford University Press
research-article |
Postnatal Toxicity following Prenatal Reserpine Exposure in Rats: Effects of Dose and Dosing Schedule
*Divisions of Teratogenesis Research, Food and Drug Administration, Department of Health and Human Services Jefferson, Arkansas 72079
Divisions of Biometry, National Center for Toxicological Research, Food and Drug Administration, Department of Health and Human Services Jefferson, Arkansas 72079
Postnatal Toxicity following Prenatal Reserpine Exposure in Rats: Effects of Dose and Dosing Schedule. BUELKE-SAM, J., KIMMEL, G. L., WEBB, P. J., SUKKER, W., JR., NEWPORT, G. D., NELSON, C. J., AND KIMMEL, C. A. (1984). Fundam. Appl. Toxicol. 4, 983–991. Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33, or 1.0 mg reserpine/kg/day either on Days 12–15 or on Days 16–19 of gestation. Dams were allowed to deliver and litters (4 ± 1 of each sex) were weighed weekly and held to 21 days of age. Basal ornithine decarboxylase (ODC) activity and neurocheraical determinations were made on hearts and brains, respectively, from pups culled from litters on postnatal Day 1, and from two males and two females/litter at 21 days of age. Following both treatment schedules, the high dose of reserpine resulted in maternal weight loss during dosing, increased stillborn pups, reduced pup weight at birth, retarded postnatal growth, and decreased survival to 21 days of age. Basal cardiac ODC activity was reduced to 33% of control levels only on Postnatal Day 1 in both high-dose groups, while absolute heart weight decreased and relative heart weight increased in these pups. Whole-brain concentrations of two neurotransmitter metabolites, 3–4-dihydroxy-phenylacctic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), were increased only at Postnatal Day 1 in the high dose group treated on Days 12–15 of gestation. No other changes were found in concentrations of these metabolites or in the transmitters dopamine and serotonin. The only effect found following administration of 0.33 mg/kg reserpine was a reduction in maternal weight gained during both dosing periods. No signs of toxicity were observed following low-dose exposure on either schedule. Most previously reported postnatal functional studies following reserpine exposure have used mid- to late-gestational treatment with 1.0 mg/kg, a dose shown here to result in marked overt maternal and fetal toxicity. Such overt toxicity raises the question of whetheT the functional effects of reserpine are primary or may be secondary to general toxic effects. Such questions must be considered when interpreting postnatal functional data and in the design of further studies.