© 1995 Oxford University Press
research-article |
Cataractogenesis in Rats Induced by in Utero Exposure to RG 12915, a 5-HT3 Antagonist
*Rhône-Poulenc Rorer Research and Development Collegeville, Pennsylvania 19426-0107 and Alfortville, France
University of Pennsylvania School of Veterinary Medicine4 Philadelphia, Pennsylvania 19104-604
Received October 13, 1994; RG 12915, a selective 5-HT3 antagonist developed for the treatment of emesis and nausea associated with cancer chemotherapy, was administered by gavage to four groups of pregnant rats from Gestation Day 6 to 17 at doses of 0, 1, 10, and 100 mg/kg/day, as part of a Segment II (developmental toxicity) study. The 100 mg/kg/day dose was maternally toxic as indicated by decreased body weight gain and food consumption during the treatment period. A portion of the rats were allowed to deliver and rear their litters and three pups from two litters in the 100 mg/kg/day group were observed to have lens opacities (visible to the naked eye) at weaning. At a later examination, when the offspring were approximately 4 months old, four additional animals from the same two litters had cataracts. A slight growth retardation was also observed postweaning in the offspring of the 100 mg/kg/day group. To confirm the lens findings and more precisely define the no-effect dose, another study was conducted in which pregnant rats were administered daily RG 12915 doses of 0, 10, 30, 60, or 100 mg/kg/day from Gestation Day 6 to 17. There was a dose-related decrement in maternal body weight gain during the treatment period in the 30, 60, and 100 mg/kg/day groups (12, 28, and 47%, respectively) compared to the control group. A treatment-related incidence of nuclear cataract was observed in the offspring of the 60 and 100 mg/kg/day groups (litter incidence 6 and 45%, respectively). Cataracts were subsequently observed in a Segment III (peri- and postnatal toxicity) study in which RG 12915 was administered to four groups of pregnant rats from Gestation Day 15 through Postpar-tum Day 21 at doses of 5, 20, and 80 mg/kg/day. A high incidence of treatment-related lens opacities was observed in the offspring of the 80 mg/kg/day group (95% of the litters were affected). Since the common treatment period between the Segment II and III studies is Gestational Days 15–17 and the major organogenesis of the lens nucleus occurs during Gestation Days 11–15 in the rat, it is suggested that the sensitive period for cataract induction by RG 12915 may be close to Gestational Day 15. In summary, maternally toxic doses of this serotonergic agent during gestation produced Cataracts in the Offspring.