The significance of genetic factors for thalidomide teratogenicity in the Norway rat

Thalidomide teratogenicity was tested on a model based on the system of congenic strains of the laboratory rat, including the mutant allele lx, which determines the polydactyly-luxate syndrome. The phenotypic expression of the allele lx changes according to the genetic background of the carrier and also according to factors of the external environment. On a hybrid genetic background LEW/BN the allele lx acts as recessive, and heterozygotes +/lx are unaffected. In a number of experiments it was proved, however, that these hybrids (LEW/BN, +/lx) had an increased sensitivity to the induction of limb malformations (polydactyly, tibial hemimelia, oligodactyly) by various teratogens. Thalidomide was administered on the 12th day of pregnancy by the intraperitoneal route in a mixture of Tween 20 with saline (1:3) in doses of 25, 50 and 200 mg/kg to females with genetic background LEW that were purposely mated with males of the BN or BN.lx strains. The produced progeny had genotypes LEW/BN, +/+ or LEW/BN, +/lx. In offsprings that had in the genotype the mutant allele lx in a heterozygous condition (+/lx) preaxial polydactyly of hind limbs developed after all the thalidomide doses tested. This malformation occurred in 17 out of 18 litters, altogether in 97 out of 162 foetuses +/lx, i.e. in 59.9%. In the progeny without the mutant allele (genotype +/+) polydactyly did not develop in any of the 108 cases. Control foetuses +/+ the mothers of which had been administered only Tween 20 with saline remained unaffected, while in control foetuses +/lx polydactyly developed in 8.1% (3 cases). The result demonstrates thalidomide teratogenicity in the laboratory rat where it has not been proved unambiguously so far. The teratogenic effect is the outcome of the interaction of thalidomide with the mutant allele lx. At the same time there is emphasized the importance of the genotype of the experimental animals in the testing of teratogens.