Institute for the Environment, Brunel University, Kingston Lane, Uxbridge, Middlesex, UK.
Toxicol Appl Pharmacol. 2011 Dec 1;257(2):189-97. doi: 10.1016/j.taap.2011.09.005. Epub 2011 Sep 16.
The risks associated with human exposures to chemicals capable of antagonising the effects of endogenous androgens have attracted considerable recent interest. Exposure is typically to large numbers of chemicals with androgen receptor (AR) antagonist activity, yet there is limited evidence of the combined effects of multi-component mixtures of these chemicals. A few in vitro studies with mixtures of up to six AR antagonists suggest that the concept of concentration addition (CA) provides good approximations of experimentally observed mixture effects, but studies with larger numbers of anti-androgens, and with more varied structural features, are missing. Here we show that the mixture effects of up to 17 AR antagonists, comprising compounds as diverse as UV-filter substances, parabens, perfluorinated compounds, bisphenol-A, benzo(α)pyrene, synthetic musks, antioxidants and polybrominated biphenyls, can be predicted well on the basis of the anti-androgenicity of the single components using the concept of CA. We tested these mixtures in an in vitro AR-dependent luciferase reporter gene assay, based on MDA-kb2 cells. The effects of further mixtures, composed of four and six anti-androgens, could be predicted accurately by CA. However, there was a shortfall from expected additivity with a ten-component mixture at two different mixture ratios, but attempts to attribute these deviations to differential expression of hormone-metabolising CYP isoforms did not produce conclusive results. CA provides good approximations of in vitro mixture effects of anti-androgens with varying structural features.
与能够拮抗内源性雄激素作用的化学物质接触相关的风险引起了人们的极大关注。接触通常涉及具有雄激素受体（AR）拮抗剂活性的大量化学物质，但这些化学物质的多成分混合物的综合影响的证据有限。少数涉及多达六种 AR 拮抗剂的混合物的体外研究表明，浓度加和（CA）概念提供了对实验观察到的混合物效应的良好近似，但缺乏具有更多种抗雄激素和更多变结构特征的研究。在这里，我们表明，多达 17 种 AR 拮抗剂的混合物效应，包括紫外线滤光剂物质、对羟基苯甲酸酯、全氟化化合物、双酚 A、苯并（α）芘、合成麝香、抗氧化剂和多溴联苯等化合物，可以基于 CA 概念使用单个成分的抗雄激素性来很好地预测。我们在基于 MDA-kb2 细胞的体外 AR 依赖性荧光素酶报告基因测定中测试了这些混合物。用 CA 可以准确预测由四种和六种抗雄激素组成的进一步混合物的效应。然而，在两种不同的混合物比例下，对于十组分混合物，存在与预期加和性的差距，但试图将这些偏差归因于激素代谢 CYP 同工型的差异表达并未产生结论性结果。CA 提供了具有不同结构特征的抗雄激素体外混合物效应的良好近似。
