Polychlorinated biphenyls (Aroclor 1254) do not uniformly produce agonist actions on thyroid hormone responses in the developing rat brain
Polychlorinated biphenyls (Aroclor 1254) do not uniformly produce agonist actions on thyroid hormone responses in the developing rat brain
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DOI：
10.1210/en.2007-1774
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Zoeller, R. Thomas
中科院分区：
文献类型：
--
作者：
Bansal, Ruby;Zoeller, R. Thomas
甲状腺激素（TH）是大脑正常发育所必需的，而多氯联苯（PCB）已知会干扰大脑发育中的TH作用。因此，在实验动物和人类中观察到的PCB暴露的神经毒性效应可能部分是通过其干扰TH信号传导的能力介导的。多氯联苯可能通过降低TH的循环水平、充当TH受体类似物或两者来干扰TH信号传导。如果多氯联苯主要通过降低血清TH水平起作用，那么它们的作用应该与低TH相似。相反，如果多氯联苯在发育中的大脑中主要作为TH激动剂，那么它们应该模仿甲状腺功能减退动物中T-4的作用。我们使用了一个双因素设计来测试这些预测。甲状腺功能减退症（Htx）和/或PCB治疗降低血清游离和总T-4出生后第15天。然而，只有Htx增加垂体TSH β表达。RC 3/neurogranin的表达减少Htx和PCB治疗增加。与此相反，浦肯野细胞蛋白-2的表达减少甲状腺功能减退的动物和PCB治疗恢复。最后，PCB处理部分改善了HTX对小脑外颗粒层厚度的影响。这些研究清楚地表明，PCB暴露不会模仿低TH对发育中大脑中几个重要TH敏感措施的影响。然而，也没有多氯联苯模拟T4甲状腺功能减退动物的所有端点测量。因此，多氯联苯在发育中的大脑中对TH信号传导发挥复杂的作用。
Thyroid hormone (TH) is essential for normal brain development, and polychlorinated biphenyls (PCBs) are known to interfere with TH action in the developing brain. Thus, it is possible that the observed neurotoxic effects of PCB exposure in experimental animals and humans are mediated in part by their ability to interfere with TH signaling. PCBs may interfere with TH signaling by reducing circulating levels of TH, acting as TH receptor analogs, or both. If PCBs act primarily by reducing serum TH levels, then their effects should mimic those of low TH. In contrast, if PCBs act primarily as TH agonists in the developing brain, then they should mimic the effect of T-4 in hypothyroid animals. We used a two-factor design to test these predictions. Both hypothyroidism (Htx) and/or PCB treatment reduced serum free and total T-4 on postnatal d 15. However, only Htx increased pituitary TSH beta expression. RC3/neurogranin expression was decreased by Htx and increased by PCB treatment. In contrast, Purkinje cell protein-2 expression was reduced in hypothyroid animals and restored by PCB treatment. Finally, PCB treatment partially ameliorated the effect of Htx on the thickness of the external granule layer of the cerebellum. These studies demonstrate clearly that PCB exposure does not mimic the effect of low TH on several important TH-sensitive measures in the developing brain. However, neither did PCBs mimic T4 in hypothyroid animals on all end points measured. Thus, PCBs exert a complex action on TH signaling in the developing brain.