Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to 6-propyl-2-thiouracil.
The present study was performed to determine target gene profiles associated with pathological mechanisms of developmental neurotoxicity. For this purpose, we selected a rat developmental hypothyroidism model because thyroid hormones play an essential role in both neuronal and glial development. Region-specific global gene expression analysis was performed at postnatal day (PND) 21 on four brain regions representing different structures and functions, i.e., the cerebral cortex, corpus callosum, dentate gyrus and cerebellar vermis of rats exposed to 6-propyl-2-thiouracil in the drinking water at 3 and 10ppm from gestational day 6 to PND 21. Expression changes of gene clusters of neuron differentiation and development, cell migration, synaptic function, and axonogenesis were detected in all four regions. Characteristically, gene expression profiles suggestive of affection of ephrin signaling and glutamate transmission were obtained in multiple brain regions. Gene clusters suggestive of suppression of myelination and glial development were specifically detected in the corpus callosum and cerebral cortex. Immunohistochemically, immature astrocytes immunoreactive for vimentin and glial fibrillary acidic protein were increased, and oligodendrocytes immunoreactive for oligodendrocyte lineage transcription factor 2 were decreased in the corpus callosum. Immunoreactive intensity of myelin basic protein was also decreased in the corpus callosum and cerebral cortex. The hippocampal dentate gyrus showed downregulation of Ptgs2, which is related to synaptic activity and neurogenesis, as well as a decrease of cyclooxygenase-2-immunoreactive granule cells, suggesting an impaired synaptic function related to neurogenesis. These results suggest that multifocal brain region-specific microarray analysis can determine the affection of neuronal or glial development.
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
Ayako
A
Shiraki
Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
Fumiyo
F
Saito
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Hirotoshi
H
Akane
Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
Masahiro
M
Takeyoshi
Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
Nobuya
N
Imatanaka
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
Megu
M
Itahashi
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Toshinori
T
Yoshida
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: mshibuta@cc.tuat.ac.jp.
Makoto
M
Shibutani
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D055495:Neurogenesis / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011441:Propylthiouracil; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000097:blood
D012333:RNA, Messenger; D013963:Thyroid Hormones; D011441:Propylthiouracil
Developmental neurotoxicity; Glial development; Hypothyroidism; Microarray; Myelination; Neurogenesis