PDF(Pubmed)
Abstract：
Elevated manganese (Mn) accumulates in the brain and induces neurotoxicity. SLC30A10 is an Mn efflux transporter that controls body Mn levels. We previously reported that full-body Slc30a10 knockout mice (1) recapitulate the body Mn retention phenotype of humans with loss-of-function SLC30A10 mutations and (2) unexpectedly develop hypothyroidism induced by Mn accumulation in the thyroid, which reduces intra-thyroid thyroxine. Subsequent analyses of National Health and Nutrition Examination Survey data identified an association between serum Mn and subclinical thyroid changes. The emergence of thyroid deficits as a feature of Mn toxicity suggests that changes in thyroid function may be an underappreciated, but critical, modulator of Mn-induced disease. To better understand the relationship between thyroid function and Mn toxicity, here we further defined the mechanism of Mn-induced hypothyroidism using mouse and rat models. Slc30a10 knockout mice exhibited a profound deficit in thyroid iodine levels that occurred contemporaneously with increases in thyroid Mn levels and preceded the onset of overt hypothyroidism. Wild-type Mn-exposed mice also exhibited increased thyroid Mn levels, an inverse correlation between thyroid Mn and iodine levels, and subclinical hypothyroidism. In contrast, thyroid iodine levels were unaltered in newly generated Slc30a10 knockout rats despite an increase in thyroid Mn levels, and the knockout rats were euthyroid. Thus, Mn-induced thyroid dysfunction in genetic or Mn exposure-induced mouse models occurs due to a reduction in thyroid iodine subsequent to an increase in thyroid Mn levels. Moreover, rat and mouse thyroids have differential sensitivities to Mn, which may impact the manifestations of Mn-induced disease in these routinely used animal models.
摘要：
升高的锰(Mn)在脑中积累并诱导神经毒性。SLC30A10是控制身体Mn水平的Mn外排转运蛋白。我们先前报道了全身Slc30a10敲除小鼠：（1）概述了具有功能丧失SLC30A10突变的人类的身体Mn保留表型；（2）出乎意料地，由甲状腺中锰的积累引起的甲状腺功能减退，减少甲状腺内甲状腺素。随后对国家健康和营养检查调查数据的分析确定了血清锰与亚临床甲状腺变化之间的关联。作为锰毒性特征的甲状腺缺陷的出现表明，甲状腺功能的变化可能被低估。但很关键,锰诱导疾病的调节剂。为了更好地了解甲状腺功能与锰毒性之间的关系，在这里，我们使用小鼠和大鼠模型进一步定义了锰诱导的甲状腺功能减退症的机制。Slc30a10敲除小鼠的甲状腺碘水平出现了严重的缺陷，该缺陷与甲状腺Mn的增加同时发生，并且在明显的甲状腺功能减退症发作之前发生。野生型锰暴露小鼠也表现出甲状腺锰水平增加，甲状腺锰和碘水平之间的负相关，亚临床甲状腺功能减退症.相比之下,尽管甲状腺Mn增加，但新生成的Slc30a10基因敲除大鼠的甲状腺碘水平没有改变，基因敲除的大鼠甲状腺功能正常。因此，在遗传或Mn暴露诱导的小鼠模型中，Mn诱导的甲状腺功能障碍是由于甲状腺Mn增加后甲状腺碘减少所致。此外，大鼠和小鼠甲状腺对锰有不同的敏感性，这可能会影响锰诱导的疾病在这些常规使用的动物模型的表现。
