基于系统性毒性研究指导全氟烷基化合物替代品设计与绿色合成

Per- and polyfluoroalkyl substances (PFASs) are indispensable chemicals in industrial and commercial applications. Legacy PFASs, typically referring to long-chain (8 perfluorinated carbons or longer) perfluoroalkyl substances, are of great concern due to their environmental persistence, bioaccumulation potential and toxicity. Thus, international regulations have been issued to reduce the production and use of legacy PFASs, and a series of other fluorinated compounds have been used as replacement. However, studies have shown that some PFAS alternatives may be even more bioaccumulative and toxic than legacy PFASs. Based on a series of techniques in analytical chemistry, organic chemistry, molecular biology and toxicology, including liquid chromatography–tandem mass spectrometry (LC-MS/MS), gas chromatography–atmospheric-pressure chemical ionization-mass spectrometry (GC-APCI-MS), quadrupole time-of-flight mass spectrometry (Q-TOF), CIC, nuclear magnetic resonance spectroscopy (NMR), molecular docking, quantitative structure–activity relationship models (QSAR), gene knock-out, RNA interference, RNA-seq, high-throughput proteomics technology, we aim to (1) investigate the occurrence, distribution and bioaccumulation potential of novel PFAS alternatives in the abiotic and biotic environment, and characterize their sources, patterns, and exposure pathways in humans; (2) develop radical fluoroalylation methodolgy and carry out the “green synthesis” of three main types of PFAS alternatives; (3) ascertain the most sensitive (critical) toxic effect and pathways by PFAS alternatives, and explore the relationship between their toxicity and chemical structure (e.g. chain length, functionalized groups, and polymerization degree); (4) elucidate the molecular mechanism of PFAS alternatives-induced hepatotoxicity, and build the forecasting models of their toxicities; (5) guide the structural design and optimization progress of novel PFAS alternatives based on toxicological data, consequently synthesize new PFAS alternatives with better performance, less bioaccumulation and less toxicity. Our project is expected to break the “lock-in” dilemma which chemicals were restricted due to adverse influences on the environment, however their alternatives were still (or even more) harmful. We aim to change this passive situation from the source, and provide some new insights in the green synthesis and toxicity testing for new chemicals.

全氟及多氟烷基化合物（PFASs）在工业应用中具有不可或缺性。由于长链PFASs带来环境污染问题，国内外已开始广泛使用PFASs替代品，但部分替代品仍具有生物累积和多种毒性效应。本项目（1）研究新型PFASs替代品在我国典型环境介质和人群血清中分布特征与累积规律，解析其来源和暴露途径；（2）发展氟烷基自由基方法，开展三大类典型PFASs替代品绿色合成。（3）基于系统性研究确定典型PFASs替代品的敏感（关键）毒性效应及关键毒性通路，阐明其结构与毒性之间的规律；（4）研究介导PFASs毒性效应的分子机制及调控途径，着重于肝毒性，构建毒性预测模型。（5）基于毒性研究成果，指导设计并优化PFASs替代品的结构，合成新的功能优异、低生物蓄积性、低毒性的替代品。本项目将有助于破解“化学品污染→替代→污染”循环往复的怪圈，从源头上改变持久性污染物被动应对的局面，为我国化学品绿色合成和毒性测试提供范例。

全氟和多氟烷基类化合物（PFASs）广泛地应用于工业和民用的多个领域，具有不可或缺性。由于长链PFASs具有持久性、累积性、长距离迁移以及多种毒性，国内外已开展了对PFASs替代品的研究并取得实质进展。但PFASs替代品呈现多样性的功能基团和多氟链段，比传统的PFASs的结构更为复杂，其环境持久性、累积性和毒性问题仍未彻底解决。本项目研究新型PFASs替代品在我国典型环境介质和人群血清中分布特征与累积规律；开展三大类典型PFASs替代品绿色合成；基于系统性研究确定典型PFASs替代品结构与毒性之间的规律；指导设计并优化PFASs替代品的结构，合成新的功能优异、低生物蓄积性、低毒性的替代品。获得以下创新性结果：（1）首次在我国环境中识别一系列新型全氟聚醚羧酸并厘清其在典型污染区域的分布特征；提出新型PFAS在重要河流中的全球性分布；发现部分新型PFAS在水生生物中的蓄积性高于传统PFAS。（2）首次获得中国普通人群PFASs暴露基线值；发现新型PFASs能透过人体重要屏障；发现部分新型PFAS暴露在脂代谢紊乱、肝、肾功能、生殖健康等方面的潜在健康效应。（3）提出新型PFASs通过激活过氧化物酶体增殖剂活化受体(PPARα，而非PPARγ)通路，干扰肝脏脂肪酸的吸收、合成和降解，导致肝脏毒性。（4）在毒性研究的指导下，构筑多样性、系列性的含氟表面活性剂，如短链全氟多醚表面活性剂，开发脱氧氟化试剂和发展一些自由基反应方法等替代品绿色合成新方法。研究结果为研发新的低毒性替代品提供支撑，为制定PFASs替代品的管理策略提供科学依据。从源头上改变持久性污染物被动应对的局面，为我国化学品绿色合成和毒性测试提供范例。.项目执行期间，发表第一标注SCI论文34篇，包括Environ Health Perspect 1篇、Environ. Sci. & Technol. 10篇。其中，ESI源高被引论文3篇，Environ. Sci. & Technol.封面文章一篇，并入选ACS Virtual Issue（中国科学院创立70周年70佳论文），相关工作被美国化学会C&EN等杂志报道多次。目前，这些文章被引1300次，单篇最高引用237次。申请专利5项。培养博士研究生13人（7人已毕业），硕士研究生6人（3人已毕业）。潘奕陶博士论文获2019年中国科学院优秀博士论文。