Retinoic acid induced myelomeningocele in fetal rats: characterization by histopathological analysis and magnetic resonance imaging.
The prevention of human neural tube defects by folic acid administration and the potential for fetal surgical intervention for myelomeningocele (MMC) have renewed interest in the molecular pathways and pathophysiology of spina bifida. Animal models for assessment of the early developmental biology and pathophysiology of this lesion are needed. The goal of this study was to develop and characterize a non-surgical rat model of MMC. Time-dated Sprague-Dawley rats were gavage fed different doses of retinoic acid (RA) dissolved in olive oil at E10 (maternal n = 55, fetal n = 505). Control animals received olive oil alone (maternal n = 20, fetal n = 265) or were untreated (maternal n = 5, fetal n = 63). Fetuses were analyzed by detailed histopathology and MRI. Overall, isolated MMC occurred in 60.7% (307/505) of RA-exposed fetuses and no controls. Histopathology confirmed the entire spectrum of severity observed in human MMC, ranging from exposure of the cord with intact neural elements to complete cord destruction. MRI of the brain of MMC fetuses confirmed structural changes similar to humans with Arnold-Chiari malformation, including downward displacement of the cerebellum to just above the foramen magnum and compression of the developing medulla into a small posterior fossa. In conclusion, the RA-induced rat model of MMC is developmentally and anatomically analogous to human MMC. This relatively efficient and cost-effective model of MMC should facilitate investigation of the developmental biology and pathophysiology of MMC, and may be useful for the evaluation of further strategies for prenatal treatment.
Danzer
E
E
The Children's Hospital of Philadelphia, The Children's Institute for Surgical Science, The University of Pennsylvania School of Medicine, Abramson Research Center, Room 1116B, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
Schwarz
U
U
Wehrli
S
S
Radu
A
A
Adzick
N S
NS
Flake
A W
AW
D000014:Abnormalities, Drug-Induced / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001139:Arnold-Chiari Malformation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003388:Cranial Fossa, Posterior / Q000002:abnormalities / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D008279:Magnetic Resonance Imaging; D008591:Meningomyelocele / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016135:Spinal Dysraphism / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D014212:Tretinoin / Q000633:toxicity*
D000970:Antineoplastic Agents; D014212:Tretinoin