Morphological and microarray analysis of T-2 toxin-induced rat fetal brain lesion.
To examine morphological and gene expression changes induced by T-2 toxin in the fetal brain in detail, pregnant rats on day 13 of gestation were treated orally with a single dose of T-2 toxin (2 mg/kg) and sacrificed at 1, 3, 6, 9, 12 and 24 h after treatment (HAT). Histopathologically, the number of apoptotic neuroepithelial cells in the telencephalon increased from 1 HAT and peaked at 12 HAT. Based on the histopathological examinations, microarray analysis was performed at 6, 12 and 24 HAT. Microarray analysis showed that the expression of oxidative stress-related genes (heat shock protein 70 (HSP70) and heme oxygenase (HO)) was strongly induced by T-2 toxin at 12 HAT, the peak time point of apoptosis induction. The expression of mitogen-activated protein kinase (MAPK)-related genes (MEKK1 and c-jun) and other apoptosis-related genes (caspase-2 and insulin-like growth factor-binding protein-3 (IGF-BP3)) was also induced by the T-2 toxin treatment. The changes observed by microarray analysis were confirmed for four up-regulated genes (HSP70, HO, IGF-BP3 and VEGF-A) using real-time RT-PCR. Our results suggest that the T-2 toxin-induced apoptosis in the fetal brain is due to oxidative stress, and that the MAPK pathway may be involved in T-2 toxin-induced toxicity.
Sehata
Shinya
S
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. sehata@sankyo.co.jp
Kiyosawa
Naoki
N
Makino
Toshihiko
T
Atsumi
Fusako
F
Ito
Kazumi
K
Yamoto
Takashi
T
Teranishi
Munehiro
M
Baba
Yasuko
Y
Uetsuka
Koji
K
Nakayama
Hiroyuki
H
Doi
Kunio
K
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D017931:DNA Primers; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013605:T-2 Toxin / Q000008:administration & dosage / Q000633:toxicity*; D013687:Telencephalon / Q000187:drug effects / Q000196:embryology
D017931:DNA Primers; D018840:HSP70 Heat-Shock Proteins; D006419:Heme Oxygenase (Decyclizing); D020928:Mitogen-Activated Protein Kinases; D013605:T-2 Toxin