Evaluation of a multiplexed, multispecies nuclear receptor assay for chemical hazard assessment.
Evaluation of a multiplexed, multispecies nuclear receptor assay for chemical hazard assessment.
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DOI：
10.1016/j.tiv.2020.105016
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发表时间：
2020-10
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影响因子：
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通讯作者：
K. Houck;Anita Simha;Audrey Bone;Jon A. Doering;S. Vliet;C. LaLone;A. Medvedev;S. Makarov
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文献类型：
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作者：
K. Houck;Anita Simha;Audrey Bone;Jon A. Doering;S. Vliet;C. LaLone;A. Medvedev;S. Makarov
对环境中潜在内分泌干扰化学物质的敏感性因物种而异，并受其核受体靶点序列保守性的影响。在这里，我们评估了一个多路复用，在玻璃法测试受体相关的内分泌和代谢干扰从五个物种。对人类核受体的TRANS-FACTORIAL™系统进行了修改，使其包括其他物种：小鼠（Mus musculus）、青蛙（Xenopus laevis）、斑马鱼（Danio rerio）、鸡（Gallus Gallus）和龟（Chrysemys picta）。包括调节内分泌功能和外源识别的受体，具体为：ERα、ERβ、AR、TRα、TRβ、PPARγ和PXR。该检测方法ECOTOX-FACTORIAL™用191种富含已知受体配体的化学物质进行评估。效价的层次聚类表明受体家族具有很强的一致性。受体家族内的种间反应比较显示，在50 μM以下的效价具有中等到高度的一致性。PPARγ在哺乳动物物种间具有较高的一致性（89%），而在哺乳动物与斑马鱼间只有63%的一致性。对于效价低于1 μM的化学物质，除PXR外，所有受体的一致性为89-100%。通过序列比对预测跨物种敏感性（sequence Alignment to Predict Across Species Susceptibility, SeqAPASS）工具获得的关键氨基酸残基与配体结合结构域序列相似性呈显著正相关。结合SeqAPASS， ECOTOX-FACTORIAL可以提供有效的重要受体筛选，以确定高优先级的影响监测物种。
Sensitivity to potential endocrine disrupting chemicals in the environment varies across species and is influenced by sequence conservation of their nuclear receptor targets. Here, we evaluated a multiplexed,in vitroassay testing receptors relevant to endocrine and metabolic disruption from five species. The TRANS-FACTORIAL™ system of human nuclear receptors was modified to include additional species: mouse (Mus musculus), frog (Xenopus laevis), zebrafish (Danio rerio), chicken (Gallus gallus), and turtle (Chrysemys picta). Receptors regulating endocrine function and xenobiotic recognition were included, specifically: ERα, ERβ, AR, TRα, TRβ, PPARγ and PXR. The assay, ECOTOX-FACTORIAL™, was evaluated with 191 chemicals enriched with known receptor ligands. Hierarchical clustering of potency values demonstrated strong coherence of receptor families. Interspecies comparisons of responses within a receptor family showed moderate to high concordance for potencies under 50 μM. PPARγ showed high concordance between mammalian species, 89%, but only 63% between mammalian and zebrafish. For chemicals with potencies below 1 μM, concordances were 89–100% for all receptors except PXR. Concordance showed a strong positive relationship to ligand-binding domain sequence similarity and critical amino acid residues obtained by the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool. In combination with SeqAPASS, ECOTOX-FACTORIAL may provide efficient screening of important receptors to identify species of high priority for effects monitoring.