title: Gene expression profiles in the fetal mouse brain after etoposide (VP-16) administration.
abstract: The aim of this study was to analyze the response of gene expression caused by etoposide (VP-16) in the fetal mouse brain. Four miligrams/kilogram of VP-16 was intraperitoneally injected into pregnant mice on day 12 of gestation (GD 12). Gene expression profiling of the VP-16-treated fetal mouse brain by DNA microarray was performed. The expression changes of the target genes of p53 were also examined by real-time RT-PCR. VP-16 induced S-phase accumulation, G2/M arrest, and eventually apoptosis of neuroepithelial cells in the fetal brain. DNA microarray analysis revealed that 8 of cell cycle control- and apoptosis-related genes were upregulated and that 5 of DNA damage, repair, replication, and transcription genes were also upregulated in the fetal telencephalons at 4 h after VP-16 treatment (HAT). The results of real-time RT-PCR demonstrated that the expression of topoisomerase IIα was increased at 4 and 8 HAT. The expression of pro-apoptotic factors such as puma, noxa, bax, and cyclin G was also increased from 4 to 12 HAT. These results suggest that VP-16 induces DNA damage, DNA repair, cell cycle alternation, and apoptosis in the fetal mouse brain. In addition, VP-16-induced apoptosis is mediated through the mitochondrial pathway in a p53-related manner. The present study will provide a better understanding of the mechanisms of VP-16-induced fetal brain injury.
authors.affiliation: Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences,The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Chunja
authors.initials: C
authors.lastname: Nam
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Xi Jun
authors.initials: XJ
authors.lastname: He
authors.forename: Gye-Hyeong
authors.initials: GH
authors.lastname: Woo
authors.forename: Byeongwoo
authors.initials: B
authors.lastname: Ahn
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Kunio
authors.initials: K
authors.lastname: Doi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D016158:Genes, p53 / Q000235:genetics*; D007274:Injections, Intraperitoneal; D008928:Mitochondria / Q000235:genetics / Q000502:physiology; D046569:Neuroepithelial Cells / Q000473:pathology; D011247:Pregnancy; D059467:Transcriptome / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D005047:Etoposide; D004250:DNA Topoisomerases, Type II