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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
Citation:
Lau, C S., M G. Narotsky, D. Lui, D S. Best, R W. Setzer, P. C. Mann, J. A. Wubah, AND T. B. Knudsen. 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. TERATOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 66(1):6-18, (2002).
Description:
Abstract
The purine analog 2-chloro-2'-deoxyadenosine (2-CdA, cladribine), an anti-leukemic and immunosuppressive agent, has been found to be teratogenic in the mouse and rabbit, causing ocular and limb defects. 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 to 60 mg/kg, at two different developmental stages, at gestational day (GD) 9.5 and GD 14. The earlier stage was chosen to match the exposure window evaluated in a previous mouse study and the later stage was selected because limb morphogenesis in the rat has been shown to be vulnerable to insults by antimetabolites (such as 5-fluorouracil) during this period. Full-litter resorption was seen in dams receiving 50 mg/kg of 2-CdA at GD 9.5, while 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. This profile of lumbar hernia and associated defects in the 2-CdA-exposed rats resembles the clinical description of lumbocostovertebral syndrome, a rare birth defect in humans that is highlighted by a lumbar hernia; thus, experimental findings from the 2-CdA teratological model may provide a key to unlock the etiology of this clinical syndrome. While 2-CdA-induced ocular defects were seen in both rat and mouse, the incidence was much lower in the rat; whereas lumbar hernia was seen only in the rat. These disparities were not readily explained by species differences in pharmacokinetic parameters. At GD 14, exposure to 2-CdA at 60 mg/kg produced oligodactyly in one of six litters. Thus, the developmental toxicity of 2-CdA is comprised of features unique to animal species as well as timing of drug exposure.