近日，卫生毒理学研究团队在二甲基甲酰胺致肝毒性机制研究领域取得重要进展。相关研究成果以“Integration of proteomics, lipidomics, and metabolomics reveals novel metabolic mechanisms underlying N, N-dimethylformamide induced hepatotoxicity”为题，在线发表在期刊Ecotoxicology and Environmental Safety（IF=4.872）（DOI: https://doi.org/10.1016/j.ecoenv.2020.111166 ）上。
二甲基甲酰胺（N, N-Dimethylformamide, DMF）是一种重要的有机溶剂，在工业生产中广泛应用，例如：纤维制造、薄膜、粘合剂、合成革等。由于其应用范围广且对人体的有害作用，美国国家环境健康研究所（NIEHS）将二甲基甲酰胺列为人类优先研究的4大化合物之一。此外，国际癌症研究机构（IARC）在2016将二甲基甲酰胺列为“可能对人类致癌（group 2A）”类物质。二甲基甲酰胺作为稳定的有机污染物，在工业废水中可以检测到，而且不易降解。二甲基甲酰胺可以通过皮肤、呼吸道或者经口吸收。吸收入体内后，其主要在肝脏进行代谢。大量的人群数据和动物实验表明，肝脏是二甲基甲酰胺毒性的靶器官。但是，至今为止二甲基甲酰胺的肝毒性机制仍然不清楚。本课题组利用人的肝原代细胞为研究工具，用二甲基酰胺染毒后，进行蛋白组，脂质组和代谢组的测序，利用联合组学的方法去解析二甲基甲酰胺致肝毒性的机制。与传统毒理学的方法相比，联合组学能够在分子水平上为毒物的毒性机制提供整体的且全面的线索，为描述细胞暴露于外来化学物质后产生的复杂的生化反应提供了直接的依据，从而为二甲基甲酰胺引起肝毒性的毒性通路提供线索。
本研究发现，二甲基甲酰胺染毒后，有284个蛋白和149个代谢产物发生变化。进一步联合蛋白组和代谢许的结果分析发现，二甲基甲酰胺暴露后主要能够扰动N-聚糖的生物合成(主要参与内质网应激和蛋白的折叠过程)，胆汁酸的代谢（参与脂质代谢和炎症反应），线粒体功能和谷胱甘肽的消耗等通路。这些发现首次在组学的层面上提供了二甲基甲酰胺诱导的肝损伤引起的蛋白和代谢产物的变化，系统的解析了二甲基甲酰胺致肝毒性的毒性通路。郑玉新教授和于典科教授为本文的通讯作者，博士研究生许琳和硕士研究生赵倩文为本文的共同第一作者。上述研究得到了国家重点研发计划项目（2017YFC1600201）和国家自然科学基金项目（91743113, 91943301, 81973075）的支持。
Recently, the research team of toxicology of our school has made great progress in the field of the mechanisms underlying DMF-induced hepatotoxicity. The related research results were published in the journal Ecotoxicology and Environmental Safety（IF=4.872) (DOI: https://doi.org/10.1016/j.ecoenv.2020.111166 ) under the title of " Integration of proteomics, lipidomics, and metabolomics reveals novel metabolic mechanisms underlying N, N-dimethylformamide induced hepatotoxicity".
N, N-Dimethylformamide (DMF), an important organic solvent, is widely used in industries such as the manufacture of fibers and films, adhesive formulations, and synthetic leather. Due to its characteristics of wide usage and adverse toxic effect in humans, National Toxicology Program of the US National Institute of Environmental Health Sciences (NIEHS) listed DMF as one of the four priority compounds for human field studies. In addition, the International Agency for Research on Cancer (IARC) has classified DMF as “probably carcinogenic to human” (group 2 A) in 2016. DMF, as a stable organic pollutant, is frequently detected in industrial effluents and prone to be introduced into the environment, and then remains unaltered in the environment withstanding a variety of physico-chemical condition. For the human, DMF is mainly absorbed through pulmonary respiration, dermal and oral. Upon absorption, DMF is mainly metabolized in the liver. Accumulating evidences obtained from animal and population studies demonstrated that the liver serves as the first target organ for toxic action of DMF. However, the mechanisms underlying DMF-induced hepatotoxicity remain poorly understood.
In this study, we systematically integrated the quantitative proteomics, lipidomics, and metabolomics data obtained from the primary human hepatocytes exposed to DMF, to depict the complicated biochemical reactions correlated to liver damage. Eventually, we identified 284 deregulated proteins (221 downregulated and 63 upregulated) and 149 deregulated lipids or metabolites (99 downregulated and 50 upregulated) induced by DMF exposure. Further, the integration of the protein-metabolite (lipid) interactions revealed that N-glycan biosynthesis (involved in the endoplasmic reticulum stress and the unfolded protein response), bile acid metabolism (involved in the lipid metabolism and the inflammatory process), and mitochondrial dysfunction and glutathione depletion (both contributed to reactive oxygen species) were the typical biochemical reactions disturbed by DMF exposure. In summary, our study identified the versatile protein, lipid, and metabolite molecules in multiple signaling and metabolic pathways involved in DMF induced liver injury, and provided new insights to elucidate the toxic mechanisms of DMF.
Prof. Yuxin Zheng and Dianke Dianke Yu were co-corresponding author of the study. Students Lin Xu, Qianwen Zhao were the co-first authors. The above research was supported by National Key R&D Program of China (Grant No. 2017YFC1600201) and National Natural Science Foundation of China (Grant No. 91743113, 91943301, and 81973075).
