新型杀菌剂噻唑锌对甲状腺素干扰作用及机制研究

Thiazole-Zn, a novel sort of thiadiazole fungicide, is a Chinese-created systemic fungicide that has been used to control bacterial diseases in China. Our previous research showed thiazole-Zn resulted in thyroid hormone imbalance, and caused thyroid follicular cell hypertrophy in rats, but little is known about the thyroid toxicity mechanism of thiazole-Zn. We put forward a hypothesis that a sustained compensatory increase in the synthesis and secretion of pituitary thyroid-stimulating hormone (TSH) occurs via a negative feedback system in response to altered thyroid gland function caused by thiazole-Zn to maintain normal levels of thyroid hormone (T3 and T4). Stimulation by TSH results in thyroid follicular cell hypertrophy and hyperplasia. Therefore, to investigate the effects of thiozole-Zn on the TH synthesis and secretion, feedback triggered by changes in the concentration of circulating THs, we will conduct an in vivo and in vitro study to analyze the thyroid disruption endpoints which comprise iodine uptake ability、iodine metabolism、Tg synthesis and secretion、mRNA-expression of the sodium-iodide-symporter (NIS)、thyroid peroxidase (TPO)、thyroglobulin (Tg)、transcription factors TTF-1and Pax8, activities of TPO in the thyroid, Furthermore, to investigate the effects of thiozole-Zn on the TH metabolism, we analyze the UDPGT activity and Dio1 activity which are associated with reduced thyroid hormone serum levels in the rat liver. According to the study which focus on the thyroid disruption endpoints including that of the synthesis of THs by the thyroid gland and its regulation by hypothalamic-pituitary hormones, the catabolism and clearance of circulating THs by the liver, we will elucidate the molecular mechanisms of thiazole-Zn-induced thyroid hyperplasia. All these work will provide great effort to thyroid disruptors screening, environmental quality control and human health promotion.

新型杀菌剂噻唑锌，系由我国首次合成，其甲状腺干扰毒性从未被提及和引起关注。前期研究首次发现噻唑锌干扰大鼠甲状腺激稳态水平，导致甲状腺增生，其毒性机理研究还未开展。本项目提出噻唑锌可能通过干扰甲状腺激素生物合成、分泌和转运途径，从而影响甲状腺激素循环水平；或在干扰甲状腺激素生物合成和分泌的同时，诱导甲状腺素代谢酶的活性，而加快甲状腺激素的代谢和排出，共同作用导致甲状腺激素水平的降低。因此，本研究拟利用甲状腺滤泡细胞FRTL-5和大鼠染毒模型，通过研究噻唑锌对甲状腺滤泡上皮细胞摄碘能力和体内碘代谢、甲状腺碘活化、甲状腺激素合成和释放以及代谢酶活性的影响；研究对调控甲状腺激素合成和转运的关键靶点基因和蛋白表达的影响。从细胞、整体和分子水平探讨噻唑锌对甲状腺干扰作用机制。阐明噻唑锌甲状腺干扰作用及机制研究，是对甲状腺干扰物研究的一次创新性补充和拓展，具有研究的价值和重要的科学理论意义。

噻唑锌是我国自主开发的新型杀菌剂，与含2-氨基-5-硫基-1,3,4-噻二唑基团的化合物统称为噻二唑类化合物。噻二唑类化合物主要由我国自行研制开发，并且主要在我国作为高毒农药的替代新品种及绿色农药被大规模推广和使用。但是这类化合物的甲状腺干扰毒性从未被引起关注，并且毒理学研究更远远落后于其应用推广的速度。基于此，本研究将阐明以噻唑锌为代表的这类化合物的甲状腺毒性特征、毒性时间效应和剂量效应关系；深入探讨其致甲状腺增生的可能机制，以期为噻二唑类化合物的人群健康风险评估和安全管理提供重要依据.. 研究结果表明，噻唑锌是一种新的甲状腺素干扰物；噻唑锌可造成大鼠甲状腺瘤发生率的升高，是一种大鼠甲状腺疑似致癌物。噻唑锌致甲状腺增生在暴露3d开始进入原发增殖期，具有明确的时间-效应关系； 噻唑锌低至16/kg.bw剂量下，引起大鼠甲状腺增生，具有明确的剂量-效应关系。噻唑锌引起甲状腺增生的机制是噻唑锌抑制甲状腺对碘的吸收，造成机体循环中的甲状腺激素（T3、T4）水平降低，机体启动下丘脑-垂体负反馈调节，反馈性的引起促甲状腺激素（TSH）的升高，从而导致甲状腺增生。