The Fischer rat thyroid follicular cell line (FRTL-5) endogenously expresses the sodium-iodide symporter (NIS) and has been used to identify environmental chemicals that perturb thyroid hormone homeostasis by disruption of NIS-mediated iodide uptake. Previously, a high-throughput radioactive iodide uptake (RAIU) screening assay incorporating the hNIS-HEK293T-EPA cell line was used to identify potential human NIS (hNIS) inhibitors in 1028 ToxCast Phase I (ph1_v2) and Phase II chemicals. In this study, the FRTL-5 cell line was evaluated and applied as a secondary RAIU assay coupled with cell viability assays to further prioritize highly active NIS inhibitors from the earlier screening. Assay validation with ten reference chemicals and performance assessment by chemical controls suggest the FRTL-5 based assays are robust and highly reproducible. Top-ranked chemicals from the ToxCast screening were then evaluated in both FRTL-5 and hNIS RAIU assays using newly sourced chemicals to strengthen the testing paradigm and to enable a rat vs. human species comparison. Eighteen of 29 test chemicals showed less than 1 order of magnitude difference in IC50 values between the two assays. Notably, two common perfluorinated compounds, perfluorooctanesulfonic acid (PFOS) and perfluorohexane sulfonate (PFHxS), demonstrated strong NIS inhibitory activity [IC50 - 6.45 (PFOS) and - 5.70 (PFHxS) log M in FRTL-5 RAIU assay]. In addition, several chemicals including etoxazole, methoxyfenozide, oxyfluorfen, triclocarban, mepanipyrim, and niclosamide also exhibited NIS inhibition with minimal cytotoxicity in both assays and are proposed for additional testing using short-term in vivo assays to characterize effects on thyroid hormone synthesis.

中文翻译：

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使用继发的Fischer大鼠甲状腺滤泡细胞（FRTL-5）放射性碘摄取（RAIU）分析评估潜在的碘化钠同向转运蛋白（NIS）抑制剂。

Fischer大鼠甲状腺滤泡细胞系（FRTL-5）内源性表达碘化钠共转运蛋白（NIS），并已用于鉴定可破坏NIS介导的碘化物摄取而扰动甲状腺激素稳态的环境化学物质。以前，使用结合了hNIS-HEK293T-EPA细胞系的高通量放射性碘摄取（RAIU）筛选试验来鉴定1028 ToxCast I期（ph1_v2）和II期化学品中潜在的人NIS（hNIS）抑制剂。在这项研究中，对FRTL-5细胞系进行了评估，并将其用作继发RAIU分析方法以及细胞生存力分析方法，以根据先前的筛选进一步确定高活性NIS抑制剂的优先级。使用十种参考化学品进行的分析验证以及通过化学对照进行的性能评估表明，基于FRTL-5的分析是可靠且高度可重复的。然后，使用新来源的化学品在FRTL-5和hNIS RAIU分析中评估了ToxCast筛选中排名最高的化学品，以增强测试范式并实现大鼠与人类之间的比较。在29种测试化学品中，有18种在两次测定之间的IC50值差异小于1个数量级。值得注意的是，两种常见的全氟化合物，全氟辛烷磺酸（PFOS）和全氟己烷磺酸盐（PFHxS），具有很强的NIS抑制活性[FRTL-5 RAIU分析中，IC50-6.45（PFOS）和-5.70（PFHxS）log M]。此外，还有几种化学药品，包括乙恶唑，甲氧芬诺，氧氟芬，三氯卡班，甲哌啶，