应用量子化学方法对羟基多溴代联苯醚的pKa预测和内分泌干扰效应的机制研究

Recently hydroxylated polybrominated diphenyl ethers (HO-PBDEs) have caused increasing environmental concern because they have been detected in the blood of fish, birds, and mammalian species and even in the abiotic environment. These chemicals contain one or more ionizable hydroxyl group(s), whose dissociation constants (pKa) could govern their partitioning in different environmental media and organisms, and then influence their potential biological activities. However there is lack of experimental pKa values for these chemicals. Furthermore, it has been shown that most of HO-PBDEs have endocrine disrupting effects, and yet the mechanism is not clear. Thus the aim of our research is to develop a quantum chemical method to estimate the pKa of HO-PBDEs from their neutral molecular structures by employing electronic structure properties-local molecular descriptors. The prediction performance of quantum chemical models will be comparatively analyzed with commercial software ACD and SPARC to develop consensus model strategy for pKa computation. Furthermore, the model performance will be validated by experimental pKa values. Basing on the pKa values, quantitative structure activity relationship (QSAR) models for estrogen disrupting effects and thyroid disrupting effects of HO-PBDEs will be developed employing local molecular descriptors. The molecular mechanism of HO-PBDEs for different hormone disruption effects will also be analyzed by the molecular simulation of several selected HO-PBDEs compounds. The results of this research could provide important physicochemical properties of HO-PBDEs for their ecological risk assessment.

目前在很多环境介质和生物体内都检测到了新兴的有机污染物羟基多溴代联苯醚(HO-PBDEs)，引起了环境科学界的广泛关注。这类化合物含有可解离的羟基基团，其酸碱解离常数(pKa)会影响它们在环境介质和生物体内的分配行为，进而影响它们潜在的生物活性。然而，目前pKa实验值尚未有报道。此外，很多研究证实了HO-PBDEs分子具有内分泌干扰效应，但作用机制尚不明确。本研究拟采用量子化学方法计算电子结构性质参数-局域分子描述符，估算HO-PBDEs的pKa值，进一步与商业软件ACD和SPARC的计算结果结合建立pKa的共识模型，并使用实验测定值进行验证。在此基础上，建立HO-PBDEs分子的雌激素和甲状腺激素效应的定量结构性质-活性关系模型(QSAR)，并选择案例化合物进行分子模拟，明确HO-PBDEs化合物对不同激素的活性干扰机制。该研究结果将为这类物质的生态风险评价提供基础数据和理论依据。

目前在很多环境介质和生物体内都监测到了新兴有机污染物羟基多溴代联苯醚(HO-PBDEs)，引起了环境科学界的广泛关注。因其含有可解离的羟基基团，pKa成为影响该类化合物在环境介质和生物体内分配进而影响其潜在生物活性的重要参数。但目前pKa实验测定值十分有限。此外，很多研究证实HO-PBDEs分子具有内分泌干扰效应，但作用机制尚不明确。本研究使用量子化学方法，设计并计算了一类新的电子结构性质参数-局域分子结构描述符，构建了能够计算该类化合物pKa值的性能良好的预测模型，并通过描述符的物理化学意义解释了影响化合物解离过程的电子和能量信息。在此基础上，使用In Silico方法揭示了HO-PBDEs化合物内分泌干扰效应的分子作用机制，并构建了预测PBDEs及其代谢产物的正辛醇-水分配系数和正辛醇-空气分配系数的QSPR模型。本研究结果一方面可以为该类化合物的生态风险评价和环境归趋研究提供重要的基础数据，另一方面有助于我们深入理解该类化合物的有害结局路径，也为研究HO-PBDEs与其他生物大分子的相互作用提供思路，将会推动该类化合物的毒理学研究进展。