The thyroid gland, a vital component of the endocrine system, plays a pivotal role in regulating metabolic processes, growth, and development. To better characterize thyroid system disrupting chemicals (TSDC), we followed the next-generation risk assessment approach, which further considers the mechanistic profile of xenobiotics. We combined targeted testing with untargeted metabolomics. Four known TSDC, propyl-thiouracil (PTU), sodium perchlorate, triclosan, and 5-pregnen-3β-ol-20-one-16α‑carbonitrile (PCN) were investigated using rat models, including primary hepatocytes, PCCL3 cells, thyroid microsomes, and three-dimensional thyroid follicles. We confirmed each compound's mode of action, PTU inhibited thyroperoxidase activity and thyroid hormones secretion in thyroid cells model, sodium perchlorate induced a NIS-mediated iodide uptake decrease as triclosan to a lesser extent, and PCN activated expression and activity of hepatic enzymes (CYPs and UGTs) involved in thyroid hormones metabolism. In parallel, we characterized intracellular metabolites of interest. We identified disrupted basal metabolic pathways, but also metabolites directly linked to the compound's mode of action as tyrosine derivates for sodium perchlorate and triclosan, bile acids involved in beta-oxidation, and precursors of cytochrome P450 synthesis for PCN. This pilot study has provided metabolomic fingerprinting of dedicated TSDC exposures, which could be used to screen and differentiate specific modes of action.

中文翻译：

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研究甲状腺干扰物的作用机制：整合体外和代谢组学分析的多模式方法


甲状腺是内分泌系统的重要组成部分，在调节代谢过程、生长和发育方面发挥着关键作用。为了更好地表征甲状腺系统干扰化学品 (TSDC)，我们采用了下一代风险评估方法，该方法进一步考虑了异生素的机制特征。我们将靶向测试与非靶向代谢组学相结合。使用大鼠模型（包括原代肝细胞、PCCL3 细胞、甲状腺微粒体）研究了四种已知的 TSDC、丙基硫氧嘧啶 (PTU)、高氯酸钠、三氯生和 5-pregnen-3β-ol-20-one-16α-腈 (PCN)和三维甲状腺滤泡。我们确认了每种化合物的作用方式，PTU 在甲状腺细胞模型中抑制甲状腺过氧化物酶活性和甲状腺激素分泌，高氯酸钠作为三氯生诱导 NIS 介导的碘吸收减少，程度较轻，PCN 激活肝酶（CYP 和 CYP）的表达和活性。 UGTs）参与甲状腺激素代谢。与此同时，我们对感兴趣的细胞内代谢物进行了表征。我们确定了被破坏的基础代谢途径，以及与该化合物的作用模式直接相关的代谢物，如高氯酸钠和三氯生的酪氨酸衍生物、参与β-氧化的胆汁酸以及PCN的细胞色素P450合成的前体。这项试点研究提供了专用 TSDC 暴露的代谢组指纹图谱，可用于筛选和区分特定的作用模式。