Harju Mikael, Hamers Timo, Kamstra Jorke H, Sonneveld Edwin, Boon Jan P, Tysklind Mats, Andersson Patrik L
Environmental Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Environ Toxicol Chem. 2007 Apr;26(4):816-26. doi: 10.1897/06-308r.1.
In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure-activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecularproperties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200-320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure-activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist.
在本研究中，建立了定量构效关系（QSARs）以辅助溴化阻燃剂（BFRs）的人体和环境风险评估过程。溴化阻燃剂，如高产量化学品多溴二苯醚（PBDEs）、四溴双酚A和六溴环十二烷，已被确定为潜在的内分泌干扰物。基于26种选定溴化阻燃剂的体外活性构建了定量构效关系模型。体外试验包括与雄激素、孕激素、雌激素和二噁英（芳烃）受体的相互作用，以及与甲状腺素竞争其血浆载体蛋白（转甲状腺素蛋白）、通过磺基转移酶抑制雌二醇硫酸化，最后是代谢速率。在QSAR建模中，计算了许多描述分子电子、亲脂性和结构特征的物理化学参数。这些参数包括前沿分子轨道、分子电荷、极性、正辛醇/水分配系数对数以及二维和三维分子性质。纳入了多溴二苯醚的实验性质并进行了测量，如它们各自的紫外光谱（200 - 320 nm）以及在三种不同的高效液相色谱柱和一种非极性气相色谱柱上的保留时间。基于雄激素拮抗作用和代谢降解速率的定量构效关系模型通常给出相似的结果，表明在邻位有溴取代且间位和对位无溴的低溴化多溴二苯醚具有最高的活性和代谢降解速率。对工业阻燃剂Bromkal 70 - 5DE成分的预测发现，BDE 17是一种有效的雄激素拮抗剂，而BDE 66（环境样品中的一种相关多溴二苯醚）只是一种弱拮抗剂。
