ToxCast PFAS化学文库对人碘化钠同转运体潜在抑制剂的高通量筛选

IF 3.8 3区 医学 Q2 CHEMISTRY, MEDICINAL
Tammy E. Stoker*, Jun Wang, Ashley S. Murr, Jarod R. Bailey and Angela R. Buckalew, 
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引用次数: 1

摘要

在过去的十年中,人们越来越关注环境化学物质,这些化学物质可以靶向下丘脑-垂体-甲状腺轴内的各个位点,从而潜在地破坏甲状腺的合成、运输、代谢和/或功能。在人类和野生动物中,一个众所周知的甲状腺靶点是碘化同调体(NIS),它调节碘进入甲状腺的吸收,这是甲状腺激素合成的第一步。我们的实验室之前在稳定转导的人类NIS细胞系(hNIS-HEK293T-EPA)中开发并验证了放射性碘吸收(RAIU)高通量测定,以鉴定具有NIS抑制潜力的化学物质。到目前为止,我们已经测试了2000多种化学物质(美国环保局的ToxCast化学库PI_v2, PII和e1K),并在hNIS分析中发现了一组显著抑制碘吸收的化学物质。在这里,我们利用这种筛选方法测试了149种独特的单氟烷基和多氟烷基物质(PFAS) (ToxCast PFAS文库)对NIS的潜在抑制作用。为了进行评估,对149份盲法样本进行了分层筛选,首先进行了初始的单浓度(≤100 μM) RAIU测试,随后使用多浓度(MC)响应(0.001-100 μM)测试,在平行RAIU和细胞活力测试中评估产生≥20%抑制作用的化学物质。在MC测试中,38种PFAS化学物质抑制碘吸收≥20%,25种显示抑制≥50%。为了优先考虑这组中最有效的PFAS NIS抑制剂,根据碘吸收和细胞毒性的结果对化学物质进行了排名,并将高氯酸盐标准化,这是一种已知的阳性对照。与先前的发现一致,PFOS和PFHxS再次被发现是有效的NIS抑制剂,但对其他几种筛选的PFAS化学物质也观察到显著的抑制作用。虽然进一步的研究显然是有必要的,但初步的筛选工作确定了NIS是这种持久性和结构多样化的化学物质潜在的甲状腺破坏的分子靶标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

High-Throughput Screening of ToxCast PFAS Chemical Library for Potential Inhibitors of the Human Sodium Iodide Symporter

High-Throughput Screening of ToxCast PFAS Chemical Library for Potential Inhibitors of the Human Sodium Iodide Symporter

Over the past decade, there has been increased concern for environmental chemicals that can target various sites within the hypothalamic–pituitary–thyroid axis to potentially disrupt thyroid synthesis, transport, metabolism, and/or function. One well-known thyroid target in both humans and wildlife is the sodium iodide symporter (NIS) that regulates iodide uptake into the thyroid gland, the first step of thyroid hormone synthesis. Our laboratory previously developed and validated a radioactive iodide uptake (RAIU) high-throughput assay in a stably transduced human NIS cell line (hNIS-HEK293T-EPA) to identify chemicals with potential for NIS inhibition. So far, we have tested over 2000 chemicals (US EPA’s ToxCast chemical libraries PI_v2, PII, and e1K) and discovered a subset of chemicals that significantly inhibit iodide uptake in the hNIS assay. Here, we utilized this screening assay to test a set of 149 unique per- and polyfluoroalkyl substances (PFAS) (ToxCast PFAS library) for potential NIS inhibition. For this evaluation, the 149 blinded samples were screened in a tiered approach, first in an initial single-concentration (≤100 μM) RAIU assay and subsequent evaluation of the chemicals that produced ≥20% inhibition using multiconcentration (MC) response (0.001–100 μM) testing in parallel RAIU and cell viability assays. Of this set, 38 of the PFAS chemicals inhibited iodide uptake ≥20% in the MC testing with 25 displaying inhibition ≥50%. To prioritize the most potent PFAS NIS inhibitors in this set, chemicals were ranked based on outcomes of both iodide uptake and cytotoxicity and normalized to perchlorate, a known positive control. Consistent with previous findings, PFOS and PFHxS were again found to be potent NIS inhibitors, yet significant inhibition was also observed for several other screened PFAS chemicals. Although further studies are clearly warranted, this initial screening effort identifies NIS as a molecular target for potential thyroid disruption by this persistent and structurally diverse class of chemicals.

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来源期刊
CiteScore
7.90
自引率
7.30%
发文量
215
审稿时长
3.5 months
期刊介绍: Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.
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