Shibutani Makoto, Woo Gye-Hyeong, Fujimoto Hitoshi, Saegusa Yukie, Takahashi Miwa, Inoue Kaoru, Hirose Masao, Nishikawa Akiyoshi
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Reprod Toxicol. 2009 Nov;28(3):297-307. doi: 10.1016/j.reprotox.2009.04.011. Epub 2009 May 4.
To clarify the developmental effects of hypothyroidism and to establish a detection system of resultant brain retardation, pregnant rats were administered 3 or 12 ppm of 6-propyl-2-thiouracil (PTU) or 200 ppm of methimazole (MMI) in the drinking water from gestation day 10 to postnatal day 20 and maintained after weaning until 11 weeks of age (adult stage). Offspring displayed evidence of growth retardation lasting into the adult stage, which was particularly prominent in males. Except for hypothyroidism-related thyroid follicular cell hypertrophy, most histopathological changes that appeared at the end of chemical exposure were related to growth retardation and reversed by the adult stage. A delayed onset of puberty and an adult stage gonadal enlargement occurred by exposure to anti-thyroid agents, both being especially evident in males, and this effect might be related to gonadal growth suppression during exposure. At the adult stage, the distribution variability of hippocampal CA1 pyramidal neurons reflecting mismigration could be detected in animals receiving both thyrotoxins, with a dose-dependent effect by PTU. Similarly, a reduction in the area of the corpus callosum and oligodendroglial cell numbers in the cerebral deep cortex, both reflecting impaired oligodendroglial development, were detected in rats administered both chemicals. Thus, all effects, except for impaired brain development, might be linked to systemic growth retardation, and the brain morphometric methods employed in this study may be useful to evaluate the potency of chemicals to induce hypothyroidism-related brain retardation.
为阐明甲状腺功能减退的发育影响并建立由此导致的脑发育迟缓检测系统，从妊娠第10天至出生后第20天，给妊娠大鼠饮用含3或12 ppm 6-丙基-2-硫脲（PTU）或200 ppm甲巯咪唑（MMI）的水，并在断奶后维持至11周龄（成年期）。后代表现出持续到成年期的生长迟缓迹象，这在雄性中尤为明显。除了与甲状腺功能减退相关的甲状腺滤泡细胞肥大外，化学物质暴露结束时出现的大多数组织病理学变化都与生长迟缓有关，并在成年期逆转。抗甲状腺药物暴露导致青春期延迟和成年期性腺增大，这在雄性中尤为明显，这种影响可能与暴露期间性腺生长抑制有关。在成年期，在接受两种甲状腺毒素的动物中可检测到反映迁移错误的海马CA1锥体神经元分布变异性，PTU呈剂量依赖性。同样，在给予两种化学物质的大鼠中，检测到胼胝体面积减小和大脑深层皮质少突胶质细胞数量减少，这两者都反映了少突胶质细胞发育受损。因此，除脑发育受损外，所有影响可能都与全身生长迟缓有关，本研究中采用的脑形态测量方法可能有助于评估化学物质诱发甲状腺功能减退相关脑发育迟缓的效力。
