近日，广东工业大学环境健康与污染控制研究院、环境科学与工程学院硕士生仇智霖和李桂英教授等人在挥发性恶臭污染物三甲胺及其代谢物对人呼吸道细胞的体外协同毒性效应方面取得最新研究进展，研究成果以《In vitro toxic synergistic effects of exogenous pollutants-trimethylamine and its metabolites on human respiratory tract cells》为题发表在《Science of the Total Environment，https://doi.org/10.1016/j.scitotenv.2021.146915》上。该研究初步揭示了三甲胺（TMA）作用于人呼吸道细胞16HBE后TMA可能的代谢途径及其作用机制，同时结合细胞毒性和氧化应激的结果，综合论证了TMA及其代谢产物对人体呼吸道细胞的协同毒性效应。

大气中挥发性恶臭有机胺的广泛存在已被证实会引起人类呼吸健康的不利影响。然而挥发性有机胺对人呼吸道的毒性效应及其在体内转化的代谢机制尚未被阐明。因此，以具有鱼腥恶臭的典型挥发性三甲胺（TMA）为例，研究了TMA急性暴露于体外培养的呼吸道上皮细胞16HBE期间细胞活力和活性氧的演化特征。与此同时为了关注TMA在人呼吸道细胞中的代谢归趋，采用PTR-TOF-MS和PTR-QMS技术对TMA及其代谢产生的挥发性中间产物进行了实时的定性和定量分析。同时也采用UPLC-QTOF-MS将直接注射的非靶标检测与丹磺酰氯标记的含胺代谢物的靶标检测相结合，对TMA在细胞和培养基中的主要代谢物进行了鉴定。结果发现随着TMA暴露浓度的增加，细胞活力逐渐下降，而ROS产生量逐渐增加。呼吸道细胞的毒性效应可能不仅由TMA本身所诱导，而且还可能由其代谢产物协同诱导。在细胞顶空以及细胞样品中鉴定到的浓度增加的二甲胺被认为是TMA的主要代谢产物，而甲胺也被证实是二甲胺进一步的代谢产物。此外TMA还可能在细胞色素P450酶的作用下，通过N-甲酰化或羟基化反应转化形成N,N-二甲基甲酰胺和N,N’-双(2-羟乙基)-1,2-乙二胺。这些鉴定出来的代谢物均比母体化合物TMA毒性更高，其中N,N-二甲基甲酰胺则更是被列为致癌物。总而言之，在恶臭有机胺暴露期间，呼吸道细胞可能产生更多的有毒代谢产物，这些代谢产物与有机胺母体化合物一起可能共同诱导细胞内的氧化应激和坏死。因此，进一步的研究和疾病风险评估除了关注有机胺这类物质之外，还应更加关注代谢物及其与母体化合物对环境和人体健康的协同影响和危害。

论文网址：https://doi.org/10.1016/j.scitotenv.2021.146915

图表摘要：

论文英文摘要：

The wide presence of volatile organic amines in atmosphere has been clarified to relate to adverse effects on human respiratory health. However, toxic effects of them on human respiratory tract and their metabiotic mechanism of in vivo transformation have not been elucidated yet. Herein, cell viability and production of reactive oxygen species (ROSs) were first investigated during acute exposure of trimethylamine (TMA) to bronchial epithelial cells (16HBE), along with identification of toxic metabolites and metabolic mechanisms of TMA from headspace atmosphere and cell culture. Results showed that cell activity decreased and ROS production increased with raising exposure TMA concentration. Toxic effect may be induced not only by TMA itself, but also more likely by its cellular metabolites. Increased dimethylamine identified in headspace atmosphere and cell solution was the main metabolite of TMA, and methylamine was also confirmed to be a further metabolite. In addition, TMA can also be oxygenated to generate N,N-dimethylformamide and N,N'-Bis(2-hydroxyethyl)-1,2-ethanediaminium by N-formylation or hydroxylation, which was considered to be the participation of cytochrome P450 (CYP) enzymes. Overall, we can conclude that respiratory tract cells may produce more toxic metabolites during exposure of toxic organic amines, which together further induce cellular oxidative stress and necrosis. Hence, the environment and health impact of metabolites as well as original parent atmospheric organic amines should be paid more attention in further researches and disease risk assessments.

资助项目：

本研究得到国家自然科学基金（41877363，42020104001和U1901210），国家重点研发项目（2019YFC1804504和2019YFC1804503）和广东珠江人才计划地方创新研究团队项目（2017BT01Z032）的基金支持。