Effects of Thalidomide on Developmental, Peri- and Postnatal Function in Female New Zealand White Rabbits and Offspring

Abstract

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.

Evaluation of the developmental toxicity of lenalidomide in rabbits

“…In particular, in the absence of any detected direct adverse effects of this dosage on the does, selective effects on development were identified including postimplantation loss, reduced live litter size, reduced fetal body weight, and multiple fetal malformations and variations, some of which were previously identified for thalidomide (Somers, 1962;Nudleman and Travill, 1971;Teo et al, 2004).…”

“…Speciesselective teratogenicity of thalidomide is well established, and many animal species do not respond similarly to humans in which thalidomide produces limb defects (Schardein, 1985;Shepard, 1989;Neubert and Neubert, 1997). Rabbits are among the species that do show limb defects similar to those observed in humans (Somers, 1962;Nudleman and Travill, 1971;Schardein, 1985;Neubert and Neubert, 1997), and studies of thalidomide in rabbits have shown that it causes multiple endpoints of developmental toxicity, including congenital malformations, postimplantation losses, abortions, reduced fetal body weights, and decreased postnatal survival of pups (Hay, 1964;Fratta et al, 1965;Nudleman and Travill, 1971;Teo et al, 2004). However, most of these studies were conducted using rabbit strains with small or no historic databases, relatively few animals, and were academic in nature, i.e., designed to identify the mechanism of action by which limb malformations were induced.…”

Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells

“…Notably, thalidomide elicited highly variable responses in the many animal species studied. In primates and a few strains of rabbits severe congenital malformations (as described above for humans) were reported, but only moderate effects were found in rats and no significant changes were observed in mice (Fratta et al, 1965;Schumacher et al, 1968;Teo et al, 2001Teo et al, , 2004. For this reason, transcriptomic studies on thalidomide have mainly used human ESCs (hESCs) (Mayshar et al, 2011;Meganathan et al, 2012).…”

“…In primates and a few strains of rabbits severe congenital malformations similar to humans were reported, but only moderate effects were found in rats and no significant changes were observed in mice (Fratta et al, 1965;Schumacher et al, 1968;Teo et al, 2001Teo et al, , 2004. The reason for mouse insensitivity to thalidomide is not well understood.…”

Aptamers for pharmaceuticals and their application in environmental analytics

“…Thalidomide exists in two enantiomeric forms, the ( R )- and ( S )-isomers which cause the differences in its biological activity. While the enantiomers can interconvert (racemize) in vivo [86], their pathogenic mechanisms are still not understood. Recently, thalidomide has been considered as a potential drug for various diseases such as autoimmune diseases, AIDS, Hansen’s disease, and some cancers [87, 88].…”