Environmental exposures often occur in complex mixtures and at low concentrations. Generalized concentration addition (GCA) is a method used to estimate the joint effect of receptor ligands that vary in efficacy. GCA models have been successfully applied to mixtures of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands, each of which can be modeled as a receptor with a single binding site. Here, we evaluated whether GCA could be applied to homodimer nuclear receptors, which have two binding sites, to predict the combined effect of full glucocorticoid receptor (GR) agonists with partial agonists. We measured transcriptional activation of GR using a cell-based bioassay. Individual dose response curves for dexamethasone (full agonist), prednisolone (full agonist), and medroxyprogesterone 17-acetate (partial agonist) were generated and applied in three additivity models, GCA, effect summation (ES), and relative potency factor (RPF), to generate response surfaces. GCA and RPF yielded adequate predictions of the experimental data for two full agonists. However, GCA fit experimental data significantly better than ES and RPF for all other binary mixtures. This work extends the application of GCA to homodimer nuclear receptors and improves prediction accuracy of mixture effects of GR agonists.

中文翻译：

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广义浓度加和法预测糖皮质激素受体配体的混合效应

环境暴露通常以复杂的混合物和低浓度发生。通用浓度加法（GCA）是一种用于评估功效不同的受体配体的联合作用的方法。GCA模型已成功地应用于芳烃受体（AhR）和过氧化物酶体增殖物激活的受体伽玛（PPARγ）配体的混合物，每种模型都可以建模为具有单个结合位点的受体。在这里，我们评估了GCA是否可以应用于具有两个结合位点的同型二聚体核受体，以预测完全糖皮质激素受体（GR）激动剂与部分激动剂的联合作用。我们使用基于细胞的生物测定法测量了GR的转录激活。地塞米松（完全激动剂），泼尼松龙（完全激动剂），生成了甲氧孕酮17醋酸酯（部分激动剂），并将其应用于GCA，效应总和（ES）和相对效能因子（RPF）这三个加性模型中，以生成响应表面。GCA和RPF对两个完全激动剂产生了足够的实验数据预测。但是，对于所有其他二元混合物，GCA拟合实验数据明显优于ES和RPF。这项工作扩展了GCA在同二聚体核受体中的应用，并提高了GR激动剂混合效应的预测准确性。对于所有其他二元混合物，GCA拟合实验数据明显优于ES和RPF。这项工作扩展了GCA在同二聚体核受体中的应用，并提高了GR激动剂混合效应的预测准确性。对于所有其他二元混合物，GCA拟合实验数据明显优于ES和RPF。这项工作扩展了GCA在同二聚体核受体中的应用，并提高了GR激动剂混合效应的预测准确性。