Developmental neurotoxicity role of cyclophosphamide on post-neural tube closure of rodents in vitro and in vivo.
To evaluate the possible developmental role of cyclophosphamide on post-neural tube closure of rodents, the 46 pregnant rats of 2.5-3 months old were randomly divided into five groups. On the 13th day of gestation, the rats in control and experimental groups were treated with physiological saline and cyclophosphamide (7.5, 10.5, 12.5 and 15.0 mg/kg bw), respectively. On the 14th day of gestation, three rats each selected randomly from control and experimental (12.5 mg/kg bw) group, respectively, were executed and the embryo brains were checked using both light microscope and transmission electron microscope. Neurocytotoxic effects of cyclophosphamide were determined using tetrazolium dye (MTT) assay, single cell gel electrophoresis, flow cytometry and scanning electron microscope. Compared with control group, the malformation incidence of the experimental groups (except the group 7.5 mg/kg bw) was significantly higher, especially in 12.5 mg/kg bw group (malformation incidence 98%, lethality 0). Neural tube serial section of fetus showed the apoptotic morphological features after 24 h cyclophosphamide administrated. Cyclophosphamide (8 microg/ml) decreased the growth and viability of neurons, damaged nuclear DNA and induced early apoptotic morphological changes. Our study shows that the teratogenesis of cyclophosphamide after neural tube closure are involved in cyclophosphamide-induced neuronal apoptosis and DNA damage.
Xiao
R
R
School of Public Health and Family Medicine, Capital Medical University, Beijing 100069, PR China.
Yu
Huan L
HL
Zhao
Hai F
HF
Liang
J
J
Feng
Jin F
JF
Wang
W
W
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000196:embryology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D003520:Cyclophosphamide / Q000633:toxicity*; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005434:Flow Cytometry; D051379:Mice; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000473:pathology*; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens; D013778:Tetrazolium Salts; D013844:Thiazoles
D017304:Annexin A5; D018906:Antineoplastic Agents, Alkylating; D013723:Teratogens; D013778:Tetrazolium Salts; D013844:Thiazoles; D003520:Cyclophosphamide; C022616:thiazolyl blue