Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to
Ayako Shiraki1, Fumiyo Saito2, Hirotoshi Akane3
1Laboratory 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.
Abstract:
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.
Insights
This study reveals how thyroid hormone deficiency impacts brain development in rats. Gene expression analysis identified region-specific changes in neuronal and glial development, affecting synaptic function and myelination.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Thyroid hormones are crucial for proper neuronal and glial development.
- Developmental neurotoxicity can lead to long-term cognitive and motor deficits.
- Understanding gene expression changes is key to identifying pathological mechanisms.
Purpose of the Study:
- To identify target gene profiles associated with developmental neurotoxicity.
- To investigate the effects of hypothyroidism on brain development in a rat model.
- To analyze region-specific gene expression changes in the developing brain.
Main Methods:
- A rat model of developmental hypothyroidism was induced using 6-propyl-2-thiouracil.
- Region-specific global gene expression analysis was performed on four brain regions at postnatal day 21.
- Immunohistochemistry was used to validate changes in specific cell types and proteins.
Main Results:
- Gene expression changes were observed in neuron differentiation, cell migration, synaptic function, and axonogenesis across all four brain regions.
- Ephrin signaling and glutamate transmission pathways were affected in multiple brain regions.
- Suppression of myelination and glial development was noted in the corpus callosum and cerebral cortex, with corresponding decreases in myelin basic protein.
- The dentate gyrus showed impaired synaptic function related to neurogenesis, indicated by Ptgs2 downregulation and reduced cyclooxygenase-2-immunoreactive cells.
Conclusions:
- Multifocal, region-specific gene expression analysis is effective in determining the impact on neuronal and glial development.
- Thyroid hormone deficiency during development causes widespread, yet region-specific, alterations in brain gene expression.
- These findings provide insights into the molecular mechanisms underlying developmental neurotoxicity.
