Metabolomics-based molecular signatures reveal the toxic effect of co-exposure to nitrosamines in drinking water
Metabolomics-based molecular signatures reveal the toxic effect of co-exposure to nitrosamines in drinking water
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基于代谢组学的分子特征揭示了同时接触饮用水中亚硝胺的毒性作用
DOI：
10.1016/j.envres.2021.111997
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发表时间：
2022
影响因子：
8.3
通讯作者：
Lihong Yin
中科院分区：
文献类型：
--
作者：
Chao Zhao;Hu Zhang;Jingjing Zhou;Qiang Lu;Lihong Yin;Xiaojin Yu;Shizhi Wang;Ran Liu;Yuepu Pu;Lihong Yin
亚硝胺是一组新兴的含氮污染物，在饮用水系统中普遍存在。然而，人们对全身生物反应如何抵抗或耐受亚硝胺，尤其是低浓度的长期共同暴露知之甚少。在这项研究中，使用非靶向代谢组学研究了饮用水中九种常见亚硝胺混合物在环境相关、人体内部暴露和基因毒性浓度下诱导的人食管上皮 Het-1A 细胞的代谢扰动。一般来说，随着亚硝胺剂量的增加，被破坏的代谢谱变得复杂。值得注意的是，两种炎症相关途径，即半胱氨酸（Cys）和蛋氨酸（MET）代谢，以及烟酸盐和烟酰胺代谢，在亚硝胺的作用下发生显着变化，即使在环境相关水平下也是如此。此外，在小鼠体内同步鉴定了细胞内的靶向代谢组学和分子生物学指标。一方面，上调的 Cys 和 MET 代谢为促炎症反应中的组蛋白甲基化提供了甲基供体。另一方面，下调的NAD+/NADH比率抑制了NF-кB p65的脱乙酰化，最终激活了NF-кB信号通路。总的来说，代谢组学分子特征是亚硝胺诱导的炎症的重要指示标记。炎症级联和代谢调节之间的潜在串扰也需要进一步研究。这些结果表明，控制饮用水中亚硝胺污染应更加重视低浓度长期共暴露。此外，这项研究还凸显了代谢组学-分子生物学相结合的方法在环境毒理学中的良好前景。
Nitrosamines, a group of emerging nitrogenous pollutants, are ubiquitously found in the drinking water system. However, less is known about how systemic biological responses resist or tolerate nitrosamines, especially long-term co-exposure at low concentrations. In this study, untargeted metabolomics was used to investigate the metabolic perturbations in human esophageal epithelial Het-1A cells induced by a mixture of nine common nitrosamines in drinking water at environmentally relevant, human-internal-exposure, and genotoxic concentrations. Generally, the disrupted metabolic spectrum became complicated with nitrosamines dose increasing. Notably, two inflammation-associated pathways, namely, cysteine (Cys) and methionine (MET) metabolism, and nicotinate and nicotinamide metabolism, changed significantly under the action of nitrosamines, even at the environmentally relevant level. Furthermore, targeted metabolomics and molecular biology indicators in cells were identified in mice synchronously. For one thing, the up-regulated Cys and MET metabolism provided methyl donors for histone methylation in the context of pro-inflammatory response. For another, the down-regulated NAD+/NADH ratio inhibited the deacetylation of NF-кB p65 and eventually activated the NF-кB signaling pathway. Taken collectively, the metabolomics molecular signatures were important indicative markers for nitrosamines-induced inflammation. The potential crosstalk between the inflammatory cascade and metabolic regulation also requires further studies. These findings suggest that more attention should be paid to long-term co-exposure at low concentrations in the control of nitrosamines pollution in drinking water. Additionally, this study also highlights a good prospect of the combined metabolomic-molecular biology approach in environmental toxicology.