Schmutzler Cornelia, Gotthardt Inka, Hofmann Peter J, Radovic Branislav, Kovacs Gabor, Stemmler Luise, Nobis Inga, Bacinski Anja, Mentrup Birgit, Ambrugger Petra, Grüters Annette, Malendowicz Ludwik K, Christoffel Julie, Jarry Hubertus, Seidlovà-Wuttke Dana, Wuttke Wolfgang, Köhrle Josef
Institut für Experimentelle Endokrinologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Environ Health Perspect. 2007 Dec;115 Suppl 1(Suppl 1):77-83. doi: 10.1289/ehp.9369.
There is growing evidence that, in addition to the reproductive system, the hypothalamic-pituitary-thyroid axis is a target of endocrine-disrupting compounds (EDCs). However, this is not reflected adequately in current screening and assessment procedures for endocrine activity that to date determine only general parameters of thyroid function.
We used several in vitro and ex vivo assays in an attempt to identify suitable biomarkers for antithyroid action testing a selected panel of putative EDCs.
In vitro we detected stimulation or inhibition of iodide uptake into FRTL-5 rat thyroid cells, inhibition of thyroid hormone binding to transthyretin, agonistic or antagonistic effects in a thyroid hormone receptor-dependent reporter assay, and inhibition of thyroid peroxidase using a novel assay system based on human recombinant thyroperoxidase that might be suitable for routine screening for potential EDCs. In rats, chronic application of several EDCs led to changes in thyroid morphology, alterations of thyrotropin and thyroid hormone serum levels as well as alterations in peripheral thyroid hormone-regulated end points such as malic enzyme and type I 5'-deiodinase activity.
As the effects of EDCs do not reflect classic mechanisms of hormone-dependent regulation and feedback, we believe multitarget and multimodal actions of EDCs affect the hypothalamic-pituitary-thyroid axis. These complex effects require a diverse approach for screening, evaluation, and risk assessment of potential antithyroid compounds. This approach involves novel in vitro or cell-based screening assays in order to assess thyroid hormone synthesis, transport, metabolism, and action as well as in vivo assays to measure thyroid hormone-regulated tissue-specific and developmental end points in animals.
越来越多的证据表明，除生殖系统外，下丘脑 - 垂体 - 甲状腺轴也是内分泌干扰化合物（EDC）的作用靶点。然而，目前的内分泌活性筛查和评估程序并未充分反映这一点，这些程序迄今为止仅能确定甲状腺功能的一般参数。
我们使用了多种体外和离体试验，试图确定用于抗甲状腺作用测试的合适生物标志物，对一组选定的假定EDC进行检测。
在体外，我们检测到FRTL - 5大鼠甲状腺细胞碘摄取的刺激或抑制、甲状腺激素与转甲状腺素蛋白结合的抑制、甲状腺激素受体依赖性报告基因检测中的激动或拮抗作用，以及使用基于人重组甲状腺过氧化物酶的新型检测系统对甲状腺过氧化物酶的抑制，该系统可能适用于潜在EDC的常规筛查。在大鼠中，几种EDC的长期应用导致甲状腺形态改变、促甲状腺激素和甲状腺激素血清水平变化，以及外周甲状腺激素调节的终点改变，如苹果酸酶和I型5'-脱碘酶活性。
由于EDC的作用并不反映激素依赖性调节和反馈的经典机制，我们认为EDC的多靶点和多模式作用会影响下丘脑 - 垂体 - 甲状腺轴。这些复杂的效应需要采用多样化的方法对潜在的抗甲状腺化合物进行筛查、评估和风险评估。这种方法包括新型体外或基于细胞的筛查试验，以评估甲状腺激素的合成、运输、代谢和作用，以及体内试验，以测量动物体内甲状腺激素调节的组织特异性和发育终点。
