Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain.
Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain were investigated. 5AzC (10 mg/kg) was injected into pregnant rats on day 13 of gestation and the protein and mRNA expressions of p53 and its transcriptional target genes, p21, bax, cyclin G1, fas, and gadd45, were examined in the foetal brain. The number of p53-positive cells peaked at 9 h after treatment (HAT) and those of apoptotic cells and p21-positive cells peaked at 12 HAT. The expressions of p21, bax, cyclin G1, and fas mRNAs were significantly elevated from 9 to 12 HAT. From the experiments using 5-bromo-2'-deoxyuridine (BrdU), as compared with controls, the migration of neuroepithelial cells significantly delayed and BrdU-positive signals were observed in many apoptotic cells from 9 to 24 HAT in the 5AzC-group. In addition, the number of S phase cells significantly decreased at 12 HAT. The present results indicate that 5AzC induced apoptosis and cell cycle arrest probably at G1 phase in the rat foetal brain and they might be mediated by p53 in response to DNA damage.
Ueno
Masaki
M
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. aa27148@mail.ecc.u-tokyo.ac.jp
Katayama
Kei-Ichi
K
Nakayama
Hiroyuki
H
Doi
Kunio
K
D000818:Animals; D017209:Apoptosis; D001374:Azacitidine / Q000633:toxicity*; D007150:Immunohistochemistry / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013687:Telencephalon / Q000187:drug effects* / Q000196:embryology* / Q000473:pathology; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016283:Proto-Oncogene Proteins p21(ras); D001374:Azacitidine