ToxSci Advance Access published online on June 30, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh207
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Celgene Corp., Warren, New Jersey
* To whom correspondence should be addressed. E-mail: steo{at}celgene.com.
The present study determined effects of thalidomide on 3 successive generations of New Zealand White rabbits after oral dosing to F0 maternal rabbits during the later 1/3 of gestation (post-major organogenesis) and lactation. One hundred and twenty four time-mated F0 rabbits (31/dose) were gavaged with 0, 30, 150 or 500 mg/kg thalidomide from gestation day 18 (DG 18) to lactation day 28 (DP or Day Postpartum 28) for approximately 42 days. At 6 months, 12 FI males and 12 F1 females were randomly paired within each dose group and mated. Reproductive evaluation and/or gross necropsy of the thoracic, abdominal and pelvic viscera was performed on day 29 post-partum (DP 29) for F0 rabbits, on DP 49 for F1 pups not selected for continued evaluation, after completion of mating for F1 rabbits and on DG 29 for F1 rabbits on continued evaluation of F2 litter. There was no thalidomide-related mortality in F0 and F1 rabbits. One F0 doe at 30 and 150 mg/kg and 2 at 500 mg/kg aborted. Maternal F0 rabbits had reductions in feed consumption but not body weight gain during the gestation and lactation periods for 150 and 500 mg/kg. The numbers of does with stillborn and all pups dying from DP 1-4 was increased at 150 and 500 mg/kg. Mean number of liveborn (litter size) and percentage of live pups were decreased at 500 mg/kg. A significantly increased number of pups died at 150 and 500 mg/kg resulting in a reduced viability index and decreased litter size. There were some F1 male and female body weight reductions at 150 and 500 mg/kg post-weaning with no change in feed consumption. F1 Caesarean-sectioning and litter observations were normal. Fertility of F1 offspring was not affected by maternal doses of thalidomide but the pregnancy index may have been reduced by the 500 mg/kg maternal thalidomide dose. There was an apparent dose-related increase in splayed limbs in F1 pups. Splaying has been reported in New Zealand White rabbits and may be a recessive trait. The splay could be caused by the nerve and muscle fiber degeneration and skeletal muscle atrophy observed in some pups. It could also be due to the decrease in litter size resulting in fewer pups per litter for nursing leading to rapid weight gain and a failure of the pups to support this weight. No F2 fetal gross external alterations were observed. In summary, pregnant rabbits orally dosed with up to 500 mg/kg thalidomide from gestation day 18 to lactation day 28 had increased abortion, changes in some natural delivery and litter parameters and limb splay in some F1 pups. No gross external changes were observed in F1 and F2 pups. 1This study was conducted in compliance with the Good Laboratory Practice Regulations (21 CFR 58) and the Animal Welfare Act of 1970 for the care of animals.
Accepted June 9, 2004
Reproductive and Developmental Toxicology
Effects of Thalidomide on Developmental, Peri- and Post-Natal Function in Female New Zealand White Rabbits and Offspring1
2 Argus Research, Divisions of Charles River Discovery and Development Services, Horsham, Pennsylvania; Milestone Biomedical Associates, Frederick, Maryland
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