Figure 4.
Figure 4. Thalidomide derivative–induced teratogenicity in CrbnI391V mice. (A) Comparison of CRBN sequences in species with and without thalidomide teratogenicity. Thalidomide teratogenicity correlates with the presence of a valine at the amino acid position corresponding with 388 in human CRBN (highlighted), whereas the presence of an isoleucine at this position predicts lack of thalidomide teratogenicity. More details about the sequences included in the alignment are in supplemental Table 3. (B) Lenalidomide induces fetal loss of CrbnI391V/I391V litters but not wild-type litters. Plugged wild-type or CrbnI391V/I391V dams who had been mated with males of the same genotype were treated with 125 mg/kg lenalidomide every 12 hours from e4.5 to e10.5. Data shown are percent of dams pregnant at e17.5. The data at bottom lists the total number of dams treated and the number pregnant at e17.5. P values are from an N-1 χ2 test. (C) Thalidomide also induces fetal demise of CrbnI391V/I391V litters but not wild-type litters. Plugged wild-type or CrbnI391V/I391V dams who had been mated with males of the same genotype were treated with 400 mg/kg thalidomide from e4.5 to e10.5. Data shown are percent of dams pregnant at harvests on e10.5 and e17.5 combined. The data at bottom lists the total number of dams treated and the number pregnant. P values are from an N-1 χ2 test. (D) Effect of lenalidomide treatment on litter size at birth. Given that lenalidomide treatment of pregnant CrbnI391V/I391V dams causes a penetrant fetal loss phenotype, data are pool of multiple experiments in which dams were treated with 25 to 125 mg/kg of lenalidomide for e4.5 to e9.5 or e4.5 to e10.5 presumed days of gestation. (E) Determination of critical period for lenalidomide treatment in mice. Each row shows a treatment schedule, with the color reflecting whether this dose and treatment schedule fetal loss phenotype. Black bars at top represent an approximate comparison with the critical period for various thalidomide-induced malformations in humans, given in days postconception. Human critical periods are from Vargesson.1 Corresponding mouse embryonic stages were assigned by comparison with Carnegie stages.52,53 P values are from an unpaired Student t test. bid, twice per day; IMiD, immunomodulatory drug.

Thalidomide derivative–induced teratogenicity in CrbnI391Vmice. (A) Comparison of CRBN sequences in species with and without thalidomide teratogenicity. Thalidomide teratogenicity correlates with the presence of a valine at the amino acid position corresponding with 388 in human CRBN (highlighted), whereas the presence of an isoleucine at this position predicts lack of thalidomide teratogenicity. More details about the sequences included in the alignment are in supplemental Table 3. (B) Lenalidomide induces fetal loss of CrbnI391V/I391V litters but not wild-type litters. Plugged wild-type or CrbnI391V/I391V dams who had been mated with males of the same genotype were treated with 125 mg/kg lenalidomide every 12 hours from e4.5 to e10.5. Data shown are percent of dams pregnant at e17.5. The data at bottom lists the total number of dams treated and the number pregnant at e17.5. P values are from an N-1 χ2 test. (C) Thalidomide also induces fetal demise of CrbnI391V/I391V litters but not wild-type litters. Plugged wild-type or CrbnI391V/I391V dams who had been mated with males of the same genotype were treated with 400 mg/kg thalidomide from e4.5 to e10.5. Data shown are percent of dams pregnant at harvests on e10.5 and e17.5 combined. The data at bottom lists the total number of dams treated and the number pregnant. P values are from an N-1 χ2 test. (D) Effect of lenalidomide treatment on litter size at birth. Given that lenalidomide treatment of pregnant CrbnI391V/I391V dams causes a penetrant fetal loss phenotype, data are pool of multiple experiments in which dams were treated with 25 to 125 mg/kg of lenalidomide for e4.5 to e9.5 or e4.5 to e10.5 presumed days of gestation. (E) Determination of critical period for lenalidomide treatment in mice. Each row shows a treatment schedule, with the color reflecting whether this dose and treatment schedule fetal loss phenotype. Black bars at top represent an approximate comparison with the critical period for various thalidomide-induced malformations in humans, given in days postconception. Human critical periods are from Vargesson.1  Corresponding mouse embryonic stages were assigned by comparison with Carnegie stages.52,53 P values are from an unpaired Student t test. bid, twice per day; IMiD, immunomodulatory drug.

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