Thalidomide malformations and genetic background in the rabbit

Sawin, P. B.; Crary, D. D.; Fox, R. R.; Wuest, H

doi:10.1007/bf02144076

Cited by 24 publications

(6 citation statements)

References 7 publications

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“…Remarkably, the teratogenic effect of thalidomide is strictly species specific. While mice and rats are thalidomide resistant, certain nonhuman primates, rabbits, and chickens show embryopathy, including a high frequency of limb truncations and microphthalmia (small eyes) upon thalidomide exposure (12,26,32).…”

mentioning

confidence: 99%

Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death

Knobloch¹,

Schmitz

Götz³

et al. 2008

Molecular and Cellular Biology

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Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomideinduced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (Bmps) protects active PTEN from proteasomal degradation, resulting in suppression of Akt signaling. As a consequence, caspase-dependent cell death is stimulated by the intrinsic and Fas death receptor apoptotic pathway. Most importantly, thalidomide-induced limb deformities and microphthalmia in chicken embryos could be rescued by a pharmacological PTEN inhibitor as well as by insulin, a stimulant of Akt signaling. We therefore conclude that perturbation of PTEN/Akt signaling and stimulation of caspase activity is central to the teratogenic effects of thalidomide.

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mentioning

confidence: 99%

Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death

Knobloch¹,

Schmitz

Götz³

et al. 2008

Molecular and Cellular Biology

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“…Some strain differences in phenotypes of the thalidomide‐induced malformations in the ear, eye, stomach, colon, kidney, heart, lung and vascular system were observed between NZW and Dutch strains (Sawin et al. ). The strain differences between NZW and Dutch were more marked than those between Kbl:JW and Kbl:NZW.…”

Section: Discussionmentioning

confidence: 99%

“…Strain differences in thalidomide teratogenicity in rabbits were also noted in comparison between NZW, mixed NZW and Dutch origin for various malformations (Sawin et al. ) and between JW (Breeder: Sebun Sangyo Co., Ltd) and JW‐NIBS (Breeder: Nippon Institute for Biological Science) for head anomalies (Matsubara et al. ).…”

Section: Introductionmentioning

confidence: 95%

“…Strain differences among the same animal species in sensitivity to teratogens have been reported, and typical examples include cleft palate induced by cortisol administration (Fraser and Fainstat 1951), some malformations induced by vitamin A treatment in rats (Nolen 1969), by biotin deficiency in mice (Watanabe and Endo 1989) and by all-trans-retinoic acid administration (Collins et al 2006). Strain differences in thalidomide teratogenicity in rabbits were also noted in comparison between NZW, mixed NZW and Dutch origin for various malformations (Sawin et al 1965) and between JW (Breeder: Sebun Sangyo Co., Ltd) and JW-NIBS (Breeder: Nippon Institute for Biological Science) for head anomalies (Matsubara et al 1983). To our knowledge, however, direct comparison in the same facility between NZW and JW rabbits has not been reported.…”

Section: Introductionmentioning

confidence: 98%

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Common nature in the effects of thalidomide on embryo‐fetal development in Kbl:JW and Kbl:NZW rabbits

Kawamura

Shirotsuka

Awatsuji

et al. 2014

Congenital Anomalies

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The effects of thalidomide on the embryofetal development (EFD) of rabbit fetuses and the sensitive periods (SP) for the various malformations were compared between Kbl:JW and Kbl:NZW rabbits to investigate possible strain differences. The post-implantation loss rate and number of placental remnants were increased and the number of live fetuses was decreased in both of the strains in the EFD study and in Kbl:NZW at 300 mg/kg dosed on GD 7-8 in the SP study. In the external and skeletal examinations, head, limb and tail malformations were observed in both the strains in the EFD and SP studies at the same dose levels in the same dosing period. In the visceral examination, hydrocephaly, cardiovascular malformations, absent pulmonary intermedial lobe, diaphragmatic hernia and/or abnormal liver lobation were also observed in both of the strains in the EFD and SP studies at the same dose levels and in the same dosing period. Plasma concentrations of thalidomide were equivalent between the two strains in the SP study. There were strain differences in some parameters, such as the post-implantation loss rate and the frequencies of malformations in forelimb and hindlimb and pulmonary intermedial lobe, but similar types of malformations or variations were induced at the same dose levels on the same dosing period in both strains. Therefore, it is concluded that there were no essential differences in sensitivity of the fetuses to thalidomide between Kbl:JW and NZW rabbits and both of the strains are useful to evaluate the teratogenic effects of thalidomide.

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“…The incidence of umbilical hernia is not unusual. Sawin et al (1965) reported umbilical hernia to occur spontaneously in 0-3.2% of the young of various rabbit strains. Control values for the occurrence of skeletal defects among fetuses of strain of rabbits employed have generally ranged from 0 to 7%.…”

Section: Three-phase Reproduction Studies In Rats and Rabbits With DCmentioning

confidence: 96%

Reproductive, teratologic, and mutagenic studies with some polydimethylsiloxanes

Kennedy¹,

Keplinger²,

Calandra³

et al. 1976

Journal of Toxicology and Environmental Health

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The purpose of these studies was to evaluate the effects of selected polydimethylsiloxanes on reproduction and fetal development in rats and rabbits and to determine the mutagenic potential of one such material in mice. In two separate three-phase studies in rats and rabbits with a 350 centistoke medical grade fluid, the only significant effect noted was an apparent dose-related incidence of in utero mortality at dose levels of 200 and 1,000 mg/kg sc in rats in one study. No evidence of fetotoxicity was obtained in the second study at the same dose levels. The incidence of talipes varus at a sc dose level of 200 mg/kg in rabbits (8.8%) is at or above that expected for control populations. The nonoccurrence of talipes varus at the higher level of 1,000 mg/kg and the absence of this defect in the companion study casts doubt on the significance of this finding. A 7-cs pump fluid was nonteratogenic in rats at oral doses as high as 1,000 mg/kg and was nonmutagenic in ma1e mice at ip doses of 5 and 10 g/kg. A 10-cs fluid was nonteratogenic in rabbits at a dermal dose level of 200 mg/kg.

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Thalidomide malformations and genetic background in the rabbit

Cited by 24 publications

References 7 publications

Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death

Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death

Common nature in the effects of thalidomide on embryo‐fetal development in Kbl:JW and Kbl:NZW rabbits

Reproductive, teratologic, and mutagenic studies with some polydimethylsiloxanes

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