Tanaka Takaharu, Masubuchi Yasunori, Okada Rena, Nakajima Kota, Nakamura Kazuki, Masuda Sosuke, Nakahara Junta, Maronpot Robert R, Yoshida Toshinori, Koyanagi Mihoko, Hayashi Shim-Mo, Shibutani Makoto
Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology.
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University.
J Toxicol Sci. 2019;44(5):357-372. doi: 10.2131/jts.44.357.
Developmental hypothyroidism as a model of autism spectrum disorders disrupts hippocampal neurogenesis through the adult stage. The present study investigated the ameliorating effect of postweaning exposure to antioxidant on the hypothyroidism-induced disruptive neurogenesis. Mated female Sprague-Dawley rats were treated with 0 or 10 ppm 6-propyl-2-thiouracil (PTU) as an anti-thyroid agent in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. PTU-exposed male offspring were fed either basal diet, diet containing α-glycosyl isoquercitrin (AGIQ) at 5,000 ppm or α-lipoic acid (ALA) at 1,000 ppm as an antioxidant from PND 21 to PND 77. PTU-exposure decreased DCX and NeuN granule cell lineage subpopulations, synaptic plasticity-related FOS granule cells, and hilar PVALB and GAD67 GABAergic interneurons, increased hilar SST and CALB2 interneurons, and upregulated Gria3, Otx2, and antioxidant enzyme genes in the dentate gyrus on PND 77. These results suggest disruption of neurogenesis remained in relation with increase of oxidative stress and compensatory responses to the disruption at the adult stage. AGIQ recovered expression of some antioxidant enzyme genes and was effective for restoration of NeuN postmitotic granule cells and PVALB and SST interneurons. In contrast, ALA was effective for restoration of all interneuron subpopulations, as well as postmitotic granule cells, and upregulated Grin2a that may play a role for the restoration. Both antioxidants recovered expression of Otx2 and AGIQ-alone recovered Gria3, suggesting a reversal of disruptive neurogenesis by compensatory responses. Thus, postweaning antioxidant exposure may be effective for ameliorating developmental hypothyroidism-induced disruptive neurogenesis by restoring the function of regulatory system.
发育性甲状腺功能减退作为自闭症谱系障碍的一种模型，会在成年期扰乱海马神经发生。本研究调查了断奶后接触抗氧化剂对甲状腺功能减退诱导的破坏性神经发生的改善作用。将交配的雌性斯普拉格-道利大鼠从妊娠第6天到出生后第21天（PND）断奶期间，在饮用水中用0或10 ppm的6-丙基-2-硫氧嘧啶（PTU）作为抗甲状腺剂进行处理。从PND 21到PND 77，将暴露于PTU的雄性后代喂食基础饮食、含有5000 ppm α-糖基异槲皮苷（AGIQ）或1000 ppm α-硫辛酸（ALA）作为抗氧化剂的饮食。在PND 77时，PTU暴露降低了双皮质素（DCX）和神经元细胞核抗原（NeuN）颗粒细胞谱系亚群、与突触可塑性相关的FOS颗粒细胞以及门区小白蛋白（PVALB）和谷氨酸脱羧酶67（GAD67）γ-氨基丁酸能中间神经元，增加了门区生长抑素（SST）和钙结合蛋白2（CALB2）中间神经元，并上调了齿状回中的谷氨酸离子型受体亚基3（Gria3）、同源盒基因Otx2和抗氧化酶基因。这些结果表明，在成年期，神经发生的破坏仍然与氧化应激的增加以及对这种破坏的代偿反应有关。AGIQ恢复了一些抗氧化酶基因的表达，并有效地恢复了NeuN有丝分裂后颗粒细胞以及PVALB和SST中间神经元。相比之下，ALA对所有中间神经元亚群以及有丝分裂后颗粒细胞的恢复有效，并上调了可能在恢复中起作用的谷氨酸离子型受体亚基2A（Grin2a）。两种抗氧化剂都恢复了Otx2的表达，且仅AGIQ恢复了Gria3的表达，这表明通过代偿反应逆转了破坏性神经发生。因此，断奶后接触抗氧化剂可能通过恢复调节系统的功能，有效改善发育性甲状腺功能减退诱导的破坏性神经发生。
