Exposure‐disease continuum for 2‐chloro‐2′‐deoxyadenosine (2‐CdA), a prototype teratogen: Induction of lumbar hernia in the rat and species comparison for the teratogenic responses

Abstract

The purine analog 2-chloro-2'-deoxyadenosine (2-CdA) caused ocular and limb defects in the mouse and rabbit. The current study examined the teratogenic potential of this drug in the rat and compared the adverse developmental outcomes with the other species. Timed-pregnant Sprague-Dawley rats were given a single intraperitoneal injection of various doses of 2-CdA ranging from 5-60 mg/kg, at gestational day (GD) 9.5 and GD 14. 2-CdA concentrations in maternal serum and embryos were measured by HPLC and termed fetuses were prepared for teratological examination. Full-litter resorption was seen in dams receiving 50 mg/kg of 2-CdA at GD 9.5, whereas post-implantation loss was significantly increased and fetal weights significantly reduced at 40 mg/kg. Gross examination of the surviving fetuses revealed microphthalmia, a shortened body trunk and lumbar hernia, manifested by a soft mass protrusion at the lumbar region on one or both sides of the spine. Incidence of these defects increased in a dose-dependent fashion. Histological examination indicated that the hernia was associated with hypoplasia of the body wall, poorly developed skeletal muscle bundles surrounding the vertebral column in the lumbar region, and an absence of the lateral muscle groups that allowed protrusion of the abdominal viscera. The lumbar hernia was generally accompanied by spina bifida, deformed ribs and a wide spectrum of soft tissue-abnormalities that included kidney, genitourinary and heart defects. At GD 14, exposure to 2-CdA at 60 mg/kg produced oligodactyly in one of six litters. 2-CdA produced similar ocular defects in the rat and mouse, although the incidence was much lower in the former species. In contrast, the drug-induced lumbar hernia was only seen in the rat. These apparent disparities were not readily explained by species differences in pharmacokinetic parameters. the similarities between the teratological features of 2-CdA-induced lumbar hernia in the rat and the clinical description of lumbocostovertebral syndrome, however, may provide a key to unlock the etiology of this rare birth defect in humans.