Ramirez Tzutzuy, Buechse Andreas, Dammann Martina, Melching-Kollmuß Stephanie, Woitkowiak Claudia, van Ravenzwaay Bennard
BASF SE Experimental Toxicology and Ecology, Carl-Bosch Str. 38, 67056 Ludwigshafen am Rhein, Germany.
BASF SE Scientific Computing, Carl-Bosch Str. 38, 67056 Ludwigshafen am Rhein, Germany.
Regul Toxicol Pharmacol. 2014 Oct;70(1):286-96. doi: 10.1016/j.yrtph.2014.07.006. Epub 2014 Jul 11.
Endocrine disrupting compounds (EDCs) of natural or synthetic origin can interfere with the balance of the hormonal system, either by altering hormone production, secretion, transport, or their binding and consequently lead to an adverse outcome in intact animals. An important aspect is the prediction of effects of combined exposure to two or more EDCs at the same time. The yeast estrogen assay (YES) is a broadly used method to assess estrogenic potential of chemicals. Besides exhibiting good predictivity to identify compounds which interfere with the estrogen receptor, it is easy to handle, rapid and therefore allows screening of a large number of single compounds and varying mixtures. Herein, we applied the YES assay to determine the potential combination effects of binary mixtures of two estrogenic compounds, bisphenol A and genistein, as well as one classical androgen that in vitro also exhibits estrogenic activity, trenbolone. In addition to generating data from combined exposure, we fitted these to a four-parametric logistic dose-response model. As all compounds tested share the same mode of action dose additivity was expected. To assess this, the Loewe model was utilized. Deviations between the Loewe additivity model and the observed responses were always small and global tests based on the whole dose-response data set indicated in general a good fit of the Loewe additivity model. At low concentrations concentration additivity was observed, while at high concentrations, the observed effect was lower than additivity, most likely reflecting receptor saturation. In conclusion, our results suggest that binary combinations of genistein, bisphenol A and trenbolone in the YES assay do not deviate from expected additivity.
天然或合成来源的内分泌干扰化合物（EDCs）可通过改变激素的产生、分泌、运输或其结合来干扰激素系统的平衡，从而在完整动物中导致不良后果。一个重要方面是预测同时接触两种或更多种EDCs的影响。酵母雌激素检测（YES）是一种广泛用于评估化学品雌激素潜力的方法。除了对识别干扰雌激素受体的化合物具有良好的预测性外，它易于操作、快速，因此可以筛选大量单一化合物和不同混合物。在此，我们应用YES检测来确定两种雌激素化合物双酚A和染料木黄酮以及一种在体外也表现出雌激素活性的经典雄激素群勃龙二元混合物的潜在联合效应。除了从联合暴露中生成数据外，我们还将这些数据拟合到一个四参数逻辑剂量反应模型中。由于所有测试化合物具有相同的作用模式，因此预期剂量相加。为了评估这一点，我们使用了洛伊模型。洛伊相加模型与观察到的反应之间的偏差总是很小，基于整个剂量反应数据集的全局测试总体上表明洛伊相加模型拟合良好。在低浓度下观察到浓度相加，而在高浓度下，观察到的效应低于相加效应，这很可能反映了受体饱和。总之，我们的结果表明，在YES检测中，染料木黄酮、双酚A和群勃龙的二元组合并未偏离预期的相加性。
