PMID- 12115775
OWN - NLM
STAT- MEDLINE
DCOM- 20030303
LR  - 20131121
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 66
IP  - 1
DP  - 2002 Jul
TI  - 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.
PG  - 6-18
AB  - 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.
CI  - Published 2002 Wiley-Liss, Inc.
FAU - Lau, Christopher
AU  - Lau C
AD  - Reproductive Toxicology Division, NHEERL, ORD, US Environmental Protection 
      Agency, Research Triangle Park, North Carolina 27711, USA. 
      lau.christopher@epa.gov
FAU - Narotsky, Michael G
AU  - Narotsky MG
FAU - Lui, Doris
AU  - Lui D
FAU - Best, Deborah
AU  - Best D
FAU - Setzer, R Woodrow
AU  - Setzer RW
FAU - Mann, Peter C
AU  - Mann PC
FAU - Wubah, Judith A
AU  - Wubah JA
FAU - Knudsen, Thomas B
AU  - Knudsen TB
LA  - eng
GR  - F31 HD08167/HD/NICHD NIH HHS/United States
GR  - T32 ES07282/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Teratogens)
RN  - 47M74X9YT5 (Cladribine)
SB  - IM
MH  - Animals
MH  - Cladribine/pharmacokinetics/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Eye Abnormalities/*chemically induced
MH  - Female
MH  - Hernia/chemically induced
MH  - Lumbosacral Region
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Spinal Cord Diseases/*chemically induced
MH  - Teratogens/*toxicity
EDAT- 2002/07/13 10:00
MHDA- 2003/03/04 04:00
CRDT- 2002/07/13 10:00
PHST- 2002/07/13 10:00 [pubmed]
PHST- 2003/03/04 04:00 [medline]
PHST- 2002/07/13 10:00 [entrez]
AID - 10.1002/tera.10039 [doi]
PST - ppublish
SO  - Teratology. 2002 Jul;66(1):6-18. doi: 10.1002/tera.10039.