Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. I: Gestational exposure.
Pergolide was given by oral gavage to mated CD-1 female mice at doses of 0, 1, 20, or 60 mg/kg/day on gestation days (GD) 6-15. Animals assigned to the teratology segment were killed on GD 18 for evaluation of maternal organ weights, and fetal viability, weights and morphology. Animals assigned to the postnatal segment were allowed to deliver and physical development and behavioral performance of the progeny were monitored until weaning. Maternal organ weights were collected at termination after weaning. One F1 offspring per sex per litter was maintained for postweaning physical, behavioral and reproductive assessments and for terminal examinations and organ weight evaluations. No adverse effects of pergolide treatment were found in the 1 mg/kg/day group. Dose-related hyperactivity, chewing and squinting that were consistent with dopaminergic stimulation occurred following dosing in the 20 and 60 mg/kg/day groups; F0 body weights and food consumption were reduced during the initial phase of treatment in the 60 mg/kg/day group. Gravid uterine weights and fetal weights were decreased in the 60 mg/kg/day group of the teratology segment, but there was no indication of teratogenicity in any group. Mammary inflammation, attributed to increased progeny suckling, occurred during the second week postpartum in a few postnatal segment females of the 20 and 60 mg/kg/day groups. Mean negative geotaxis performance was delayed slightly, but mean progeny survival and body weights were not affected. Although after weaning the F1 offspring from the treatment-derived groups tended to weigh more than controls and to perform more effectively in the active avoidance task, these findings were attributed to unusually low values obtained in the control group. Startle amplitudes were increased significantly in the males from the 60 mg/kg/day treatment-derived group. These dose-related maternal and developmental findings were all consistent with the mixed D1/D2 agonist properties of pergolide mesylate, and suggest that only very high doses may result in persistent effects on the developing central dopaminergic systems.
Buelke-Sam
J
J
Toxicology Research Laboratories, Eli Lilly & Company, Greenfield, IN 46140.
Byrd
R A
RA
Johnson
J A
JA
Tizzano
J P
JP
Owen
N V
NV
D000375:Aging; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D005260:Female; D005313:Fetal Death; D005333:Fetus / Q000187:drug effects*; D008098:Litter Size / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009498:Neurotoxins; D009929:Organ Size / Q000187:drug effects; D010479:Pergolide / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D012727:Sex Characteristics; D013723:Teratogens; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D009498:Neurotoxins; D013723:Teratogens; D010479:Pergolide