Skeletal malformations in the Holtzman rat embryo following the administration of thalidomide

Abstract

ABSTRACT Pregnant Holtzman albino rats were given 25-, 50- or 500-mg. doses of thalidomide intraperitoneally, or by stomach tube, during the time their embryos’ limbs were developing. Except in rare instances, thalidomide had no effect on limb development. In one case, limb malformations closely resembling thalidomide deformities in man and rabbits were observed. The commonest effect of thalidomide on rat development was absent, delayed, or abnormal ossification of the 5th sternebra. The most serious abnormalities observed were maldevelopment, fusion or absence of vertebrae. Other skeletal defects observed occasionally were: ‘scrambled’ sternebrae, abnormal flexion of toes, ‘clubfoot ‘, absence of vertebrae, ribs and tail and supernumerary ribs. In general the 50-mg. dose of thalidomide induced the most serious defects. The method of administration (by stomach tube or by intraperitoneal injection) seemed to make no difference. The critical period during which thalidomide seems to act on the skeletal system in this strain of rat is from the 10th to 12th days of gestation. Some control fetuses had minor skeletal defects suggesting that sodium carboxymethylcellulose may also be a weak teratogen in this strain of rat. The thalidomide-produced vertebral and sternebral defects were not visible during macroscopic examination. Alizarin preparations were needed to demonstrate the defects; this suggests that the above technique should be a part of all investigations aimed at detecting teratogenicity of drugs.