Toxicity Assessment Division, Neurotoxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
Neuroscience. 2013 Jun 3;239:253-70. doi: 10.1016/j.neuroscience.2012.11.022. Epub 2012 Nov 29.
Thyroid hormones (TH) are essential for normal brain development. Even modest degrees of TH disruption experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth. Neurotrophins have been implicated in a host of brain cellular functions, and in particular, brain-derived neurotrophic factor (BDNF) has a well documented role in development and function of the nervous system. A number of laboratories have reported the effects of TH administration or severe deprivation on neurotrophin expression in brain. This review provides an overview and update of recent developments in the thyroid field as they relate to the nervous system. Secondly, we describe an animal model of low level TH insufficiency that is more relevant for studying the neurological consequences associated with the modest TH perturbations of subclinical hypothyroidism, or that would be anticipated from exposure to environmental contaminants with a mode-of-action that involves the thyroid. Finally, we review the available in vivo literature on TH-mediated alterations in neurotrophins, particularly BDNF, and discuss their possible contribution to brain impairments associated with TH insufficiency. The observations of altered BDNF protein and gene expression have varied as a function of hypothyroid model, age, and brain region assessed. Only a handful of studies have investigated the relationship of neurotrophins and TH using models of TH deprivation that are not severe, and dose-response information is sparse. Differences in the models used, species, doses, regions assessed, age at assessment, and method employed make it difficult to reach a consensus. Based on the available literature, the case for a direct role for BDNF in thyroid-mediated effects in the brain is not compelling. We conclude that delineation of the potential role of neurotrophins in TH-mediated neuronal development may be more fruitful by examining additional neurotrophins (e.g., nerve growth factor), moderate degrees of TH insufficiency, and younger ages. We further suggest that investigation of BDNF invoked by synaptic activation (i.e., plasticity, enrichment, trauma) may serve to elucidate a role of thyroid hormone in BDNF-regulated synaptic function.
甲状腺激素（TH）对正常脑发育至关重要。即使在子宫内经历适度程度的 TH 干扰，也会导致儿童出现神经心理缺陷，尽管出生时甲状腺功能正常。神经营养因子参与了许多大脑细胞功能，特别是脑源性神经营养因子（BDNF）在神经系统的发育和功能中具有明确的作用。许多实验室报告了 TH 给药或严重剥夺对脑中神经营养因子表达的影响。这篇综述提供了甲状腺领域与神经系统相关的最新发展的概述和更新。其次，我们描述了一种低水平 TH 不足的动物模型，该模型与研究与亚临床甲状腺功能减退症适度 TH 干扰相关的神经后果或与作用模式涉及甲状腺的环境污染物暴露相关的神经后果更相关。最后，我们回顾了 TH 介导的神经营养因子，特别是 BDNF 改变的可用体内文献，并讨论了它们对与 TH 不足相关的脑损伤的可能贡献。BDNF 蛋白和基因表达的改变因甲状腺功能减退模型、年龄和评估的脑区而异。只有少数研究调查了使用不是严重的 TH 剥夺模型的神经生长因子与 TH 之间的关系，并且剂量反应信息很少。使用的模型、物种、剂量、评估区域、评估年龄和使用的方法不同，使得很难达成共识。基于现有文献，BDNF 在甲状腺介导的大脑效应中直接发挥作用的情况并非确凿无疑。我们得出的结论是，通过检查其他神经营养因子（例如神经生长因子）、适度程度的 TH 不足和更年轻的年龄，进一步研究神经生长因子在 TH 介导的神经元发育中的潜在作用可能更有成效。我们进一步建议，研究由突触激活（即可塑性、富集、创伤）引发的 BDNF 可能有助于阐明甲状腺激素在 BDNF 调节的突触功能中的作用。
