Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Arch Toxicol. 2012 Oct;86(10):1559-69. doi: 10.1007/s00204-012-0846-y. Epub 2012 Mar 31.
Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.
甲状腺功能减退症会影响神经发生。本研究旨在阐明甲状腺功能减退症在发育和成年阶段对海马齿状回神经发生相关细胞反应的敏感性。使用从妊娠第 10 天到出生后第 21 天（发育性甲状腺功能减退症）的怀孕大鼠和设置相同暴露期的成年雄性大鼠（从出生后第 46 天到第 77 天），用饮用水中的甲巯咪唑（MMI）作为抗甲状腺药物进行暴露研究，浓度分别为 0、50 和 200ppm。发育性甲状腺功能减退症的后代在出生后第 21 天或第 77 天处死，成年甲状腺功能减退症的动物在第 77 天处死。齿状回颗粒下区的增殖和凋亡在发育性或成年甲状腺功能减退症中均无变化。至于前体细胞颗粒细胞，在发育性甲状腺功能减退症中，50 和 200ppm 的 MMI 持续减少配对盒 6 阳性的干细胞或早期祖细胞，短暂减少双皮质素阳性的晚期祖细胞，而成年甲状腺功能减退症则无变化。在齿状回门区的γ-氨基丁酸（GABA）能中间神经元亚群中，在 50 和 200ppm 的 MMI 诱导的发育性和成年甲状腺功能减退症中，减少了钙结合蛋白 1 阳性细胞的数量，增加了钙结合蛋白 2 阳性细胞的数量。用 200ppm 的 MMI 诱导的发育性甲状腺功能减退症中 GABA 能中间神经元数量的波动一直持续到出生后第 77 天。考虑到 GABA 能中间神经元亚群在神经发生和神经元分化中的作用，甲状腺功能减退症引起的 GABA 能中间神经元亚群的变化可能是异常神经发生的特征，甚至在成年期也是如此。
