Effects of thalidomide on developmental, peri- and postnatal function in female New Zealand white rabbits and offspring.
The present study determined effects of thalidomide on three successive generations of New Zealand White rabbits after oral dosing to F0 maternal rabbits during the later third 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 F1 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 postpartum (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 postweaning 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.
Teo
Steve K
SK
Celgene Corp., 7 Powder Horn Drive, Warren, New Jersey 07059, USA. steo@celgene.com
Denny
Kevin H
KH
Stirling
David I
DI
Thomas
Steve D
SD
Morseth
Sandy
S
Hoberman
Alan M
AM
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000019:Abortifacient Agents / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004622:Embryo, Mammalian / Q000473:pathology / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000473:pathology; D017880:Limb Deformities, Congenital / Q000139:chemically induced / Q000473:pathology; D008892:Milk / Q000737:chemistry; D009422:Nervous System Diseases / Q000139:chemically induced / Q000473:pathology; D036801:Parturition / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011817:Rabbits; D012098:Reproduction / Q000187:drug effects; D012726:Sexual Behavior, Animal / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects; D013696:Temperature; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*; D013792:Thalidomide / Q000493:pharmacokinetics / Q000633:toxicity*
D000019:Abortifacient Agents; D013723:Teratogens; D013792:Thalidomide