Perinatal exposure to PTU delays switching from NR2B to NR2A subunits of the NMDA receptor in the rat cerebellum.
Certain kinds of developmental neurotoxicants are considered to act by affecting the levels of thyroid hormones, which are essential for the brain development of both humans and experimental animals. Hypothyroidism experimentally induced in rats with propylthiouracil (PTU) offers a useful animal model for developmental neurotoxicity. The purpose of the present study was to clarify developmental alterations in gene expression caused by PTU in this model, with the focus on eight genes implicated in neural network formation or synaptic functions, such as the brain-derived neurotrophic factor (BDNF) and NMDA receptors 2A/2B. First, we measured the developmental profile of gene expression in vehicle-dosed rat cerebellum by quantitative RT-PCR and then examined the effects of PTU on mRNA levels on postnatal day (PND) 22, when most of the cerebellar structures in mature animals are already formed. PTU induced up-regulation of NR2B mRNA and down-regulation of NR2A and BDNF mRNAs in the cerebellum on PND 22, but there were no changes in the other genes (growth associated protein-43, L1, neuronal cell adhesion molecule, synaptophysin, post synaptic density-95). Examination of the effects of PTU on maturation of NMDAR subunits (NR2A/NR2B) demonstrated changes in relative expression on PND 14, but not on PND 4, with recovery after maturation. The profile of NMDAR subunits in vehicle-dosed rats showed a shift from NR2B to NR2A during development. These results suggest PTU can delay this switching from NR2B to NR2A subunits in the maturation of NMDA receptors.
Kobayashi
Kumiko
K
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan. kobayashik7@sc.sumitomo-chem.co.jp
Tsuji
Ryozo
R
Yoshioka
Takafumi
T
Mino
Terumasa
T
Seki
Takaki
T
D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D011247:Pregnancy; D011441:Propylthiouracil / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D013956:Antithyroid Agents; D019208:Brain-Derived Neurotrophic Factor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D011441:Propylthiouracil