Hearing loss in athyroid Pax8 knockout mice and effects of thyroxine substitution
Hearing loss in athyroid Pax8 knockout mice and effects of thyroxine substitution
复制标题
DOI：
10.1159/000076000
复制
发表时间：
2004-01-01
影响因子：
1.6
通讯作者：
Smolders, JWT
中科院分区：
文献类型：
--
作者：
Christ, S;Biebel, UW;Smolders, JWT
Pax 8-/-小鼠不发育甲状腺滤泡结构，因此为研究先天性甲状腺功能减退症的后果提供了理想的动物模型。尽管它们的甲状腺功能减退，Pax 8-/-小鼠存活至出生后第21天（P21）。在130 dB SPL时，即使在P21，当对照小鼠的听力达到成年灵敏度时，这些动物也不能记录到对声音的听觉脑干反应（ABR）。在相当大比例的Pax 8-/-动物中发现外耳和中耳结构中的Abstraction。相对于甲状腺功能正常的对照组，内耳的成熟似乎延迟了约1周。成年Pax 8-/-小鼠的听力可以通过出生后早期用甲状腺素（T-4）替代而几乎正常化，但听力的结构和功能恢复不完全。即使在P1时开始T-4替代，在6周龄或更大时测量的ABR阈值也增加了约20 dB，并且T-4替代开始的每一天延迟导致额外的阈值损失约4 dB。在Pax 8-/-动物中，T-4取代在P8或更晚开始的最突出的结构缺陷是异常厚的盖膜。在这些晚期替代动物中，观察到内毛细胞和外毛细胞的立体绒毛排列紊乱，还发现外毛细胞丢失，主要发生在耳蜗的基底部。随着T-4取代开始时间的延长，结构紊乱程度增加。在Pax 8-/-小鼠中观察到的出生后甲状腺功能减退的结构和功能后果在很大程度上与从甲状腺功能减退动物模型中获得的数据一致并延伸，其中甲状腺功能减退是由甲状腺肿剂（甲巯咪唑，丙基硫氧嘧啶）或TSH受体或甲状腺激素受体基因被破坏的动物模型诱导的。Pax 8-/-小鼠的听力损失和T-4替代的恢复效果大于其他模型。尽管Pax 8-/-小鼠由甲状腺功能正常的Pax 8 +/-母鼠出生，但Pax 8-/-表型不能通过出生后立即的T-4替代而完全恢复，这表明某些缺陷是后代产前T-4缺陷的结果。版权所有（C）2004 S. Karger AG，巴塞尔。
Pax8-/- mice do not develop thyroid follicular structures and thus provide an ideal animal model to study the consequences of congenital hypothyroidism. Despite their athyroidism, Pax8-/- mice survive up to postnatal day 21 (P21). No auditory brain stem responses (ABR) to sound could be recorded in these animals at 130 dB SPL, even at P21, when hearing reaches adult sensitivity in control mice. Abnormalities in the outer and middle ear structures were found in a considerable percentage of Pax8-/- animals. Maturation of the inner ear appeared delayed by about 1 week with respect to euthyroid controls. Hearing of adult Pax8-/- mice could be nearly normalized by early postnatal substitution with thyroxine (T-4), but structural and functional restoration of hearing was incomplete. Even when T-4 substitution was initiated at P1, ABR thresholds, measured at 6 weeks of age or more, were increased by about 20 dB, and each day of delay in the start of T-4 substitution resulted in an additional threshold loss of about 4 dB. The most prominent structural deficit in Pax8-/- animals in which T-4 substitution was started at P8 or later was an abnormally thick tectorial membrane. In these late-substituted animals, disarray of stereovilli from inner and outer hair cells was observed and also outer hair cell loss was found, predominantly in the basal part of the cochlea. The degree of structural disorder increased the later T-4 substitution was initiated. The structural and functional consequences of postnatal athyroidism observed in Pax8-/- mice are largely in agreement with and extend those data obtained from hypothyroid animal models in which hypothyroidism was induced by goitrogenic agents ( methimazole, propylthiouracil) or animal models with disrupted genes for the TSH receptor or the thyroid hormone receptors. The hearing loss and also the recovery effect by T-4 substitution in Pax8-/- mice is larger than that in the other models. Although Pax8-/- mice are born by euthyroid Pax8+/- dams, the Pax8-/- phenotype could not be completely restored by immediate postnatal T-4 substitution, indicating that some deficits are the consequence of prenatal T-4 deficiency of the offspring. Copyright (C) 2004 S. Karger AG, Basel.