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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Ventral prostate predominant l, a novel mouse gene expressed exclusively in the prostate.

BACKGROUND: Despite the region-specific nature of human prostate disease, there is a paucity of information regarding the molecular basis of prostate regionalization and patterning. To elucidate genetic mechanisms that underlie prostate growth and development, we investigated differential gene expression in mouse prostate lobes. METHODS: mRNA differential display analysis was used to identify differentially expressed genes during development of ventral, anterior, and dorsolateral prostate lobes. Differential gene expression was confirmed by Northern blot analysis and RT-PCR. RESULTS: A novel gene, Ventral prostate predominant1 (Vpp1) was identified. Vpp1 mRNA was evident in all lobes but accumulated predominantly in the ventral prostate, and was detected on postnatal day 7 through adulthood exclusively in the prostate gland. The steady-state level of Vpp1 mRNA decreased markedly in response to castration, suggesting androgen regulation of Vpp1 expression. Analysis of TRAMP tumors demonstrated a dramatic decrease in the level of Vpp1 mRNA. CONCLUSIONS: The spatial distribution and early postnatal onset of Vpp1 expression is consistent with a role for this gene in prostate regionalization. The absolute prostate specificity of Vpp1 expression may allow this gene to serve as a paradigm to study the molecular basis of gene expression that is restricted exclusively to the prostate gland.