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DEVELOPMENTAL TOXICITY OF 2-CHLORO-2'-DEOXYADENOSINE IN THE RAT: INDUCTION OF LUMBAR HERNIA
Citation:
Lau, C S., M G. Narotsky, D. Lui, D S. Best, R W. Setzer, AND T. B. Knudsen. DEVELOPMENTAL TOXICITY OF 2-CHLORO-2'-DEOXYADENOSINE IN THE RAT: INDUCTION OF LUMBAR HERNIA. Presented at Society of Toxicology, San Francisco, CA, March 25 - 29, 2000.
Description:
DEVELOPMENTAL TOXICITY OF 2-CHLORO-2'DEOXYADENOSINE IN THE RAT: INDUCTION OF LUMBAR HERNIA. C. Lau1, M.G. Narotsky1, D. Lui1, D. Best1, R.W. Setzer2, T.B. Knudsen3. 1Reprod. Tox. Div., 2Exp. Tox. Div., NHEERL, US EPA, Research Triangle Park, NC, USA, 3Dept. Path. Anat. Cell Biol., Jefferson Med. Coll., Philadelphia, PA, USA. Sponsor: J.E. Andrews.
The purine analog 2-chloro-2'-deoxyadenosine (2-CdA, cladribine) is an anti-leukemic and immunosuppressive agent, but has been found to be teratogenic in the mouse, causing eye and limb defects. For comparison, the current study examined the teratogenic potential of this drug in the rat. Timed-pregnant Sprague-Dawley rats were given a single injection of 2-CdA (i.p., at 15, 25, 30, 40 or 50 mg/kg) on GD-9.5 (0-4 somite stage). Controls received saline. Full litter resorption was seen in dams receiving 50 mg/kg of 2-CdA, while post-implantation loss was significantly increased and fetal weights were significantly reduced at 40 mg/kg. Gross examination of the surviving fetuses revealed microphthalmia, a shortened body trunk and lumbar hernia. The hernia entailed a soft mass protruded 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 of abdominal viscera 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. The lumbar hernia was generally accompanied by spina bifida, deformed ribs and a host 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 congenital lumbar hernia; thus, experimental findings from the 2-CdA teratological model may provide a key to unlock the etiology of this clinical syndrome. While the 2-CdA-induced ocular defects were seen in both rat and mouse, the incidence was much lower in the former species; whereas lumbar hernia appeared to be unique to the rat. These disparities were not readily explained by species differences in pharmacokinetic parameters. Thus, 2-CdA is teratogenic in both rodent species but the characteristics are markedly different. (This abstract does not reflect US EPA policy.)