Department of Emergency Medicine, The First Affiliated Hospital and Department of Environmental Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Environ Int. 2022 Mar;161:107139. doi: 10.1016/j.envint.2022.107139. Epub 2022 Feb 13.
Cd exposure has been demonstrated to induce a variety of metabolic disorders accompanied with imbalance of glucose and lipid homeostasis. The metabolic toxicity of Cd exposure at metabolome-wide level remains elusive. In our study, we demonstrated that Cd exposure via drinking water increased blood glucose levels, decreased serum insulin levels, led to glucose intolerance and suppressed insulin expression in the pancreas of C57/6J mice. Cd exposure significantly inhibited cell viability and suppressed insulin secretion in MIN6 cells in vitro. Since pancreatic β-cells are the only source of insulin production in the body and play a pivotal role in modulating glucose and lipid metabolisms, we further delineated the metabolomic signatures of Cd exposure in insulin-secreting MIN6 cells by using non-target metabolomics. PCA and OPLS-DA analysis clearly suggested that Cd exposure led to a marked metabolic alteration in MIN6 cells. 76 perturbed metabolites were identified after Cd exposure. Classification of metabolites suggested that Cd perturbed metabolites belong to nucleosides, nucleotides and analogues, organic acids and derivatives, and lipids and lipid-like molecules. 28 perturbed metabolites existed in mitochondrion, suggesting mitochondrion as the major target organelle in metabolic toxicity of Cd exposure. KEGG pathway analysis revealed that 20 metabolic pathways were disturbed by Cd exposure. Mitochondrial TCA cycle and glycerophospholipid metabolism were remarkably disturbed. The mRNA expressions of genes in mitochondrial TCA cycle and fatty acid oxidation in pancreas and MIN6 cells were significantly dysregulated by Cd exposure. Disturbances in mitochondrial TCA cycle and glycerophospholipid metabolism result in producing perturbed metabolites in pancreatic β-cells. Moreover, 14 perturbed metabolites identified in MIN6 cells co-existed in the urine of Cd exposed workers. 11 biomarkers of diabetes mellitus were also found to be significantly altered in the urine of Cd exposed workers. In conclusion, findings of this study greatly extend our understanding of metabolic toxicity of Cd exposure in pancreatic β-cells at metabolome-wide level and offer some new clues for linking Cd exposure to development of diabetes mellitus. Results of this study also support the notion that Cd induced metabolic toxicity could be monitored by examining perturbed urinary metabolites in humans and highlight the significance of reducing Cd exposure via drinking water at population level.
镉暴露已被证实可诱导多种代谢紊乱，并伴有葡萄糖和脂质稳态失衡。镉暴露在代谢组学水平上的代谢毒性仍不清楚。在本研究中，我们证明了通过饮用水摄入镉会导致 C57/6J 小鼠的血糖水平升高，血清胰岛素水平降低，导致葡萄糖耐量降低，并抑制胰腺中的胰岛素表达。镉暴露在体外显著抑制 MIN6 细胞的细胞活力和胰岛素分泌。由于胰腺β细胞是体内胰岛素产生的唯一来源，在调节葡萄糖和脂质代谢中起着关键作用，因此我们通过非靶向代谢组学进一步描绘了胰岛素分泌 MIN6 细胞中镉暴露的代谢特征。PCA 和 OPLS-DA 分析清楚地表明，镉暴露导致 MIN6 细胞发生明显的代谢改变。镉暴露后鉴定出 76 个扰动代谢物。代谢物分类表明，镉扰动代谢物属于核苷、核苷酸及其类似物、有机酸及其衍生物以及脂质和类脂分子。28 个扰动代谢物存在于线粒体中，表明线粒体是镉暴露代谢毒性的主要靶细胞器。KEGG 通路分析显示，20 个代谢途径受到镉暴露的干扰。线粒体三羧酸 (TCA) 循环和甘油磷脂代谢受到明显干扰。镉暴露还显著调节胰腺和 MIN6 细胞中线粒体 TCA 循环和脂肪酸氧化相关基因的 mRNA 表达。线粒体 TCA 循环和甘油磷脂代谢的紊乱导致胰腺β细胞中产生扰动代谢物。此外，在镉暴露工人的尿液中还鉴定出 14 种在 MIN6 细胞中存在的扰动代谢物。在镉暴露工人的尿液中还发现 11 种糖尿病生物标志物也发生了显著改变。总之，本研究的结果大大扩展了我们对胰腺β细胞中镉暴露代谢毒性的认识，为将镉暴露与糖尿病的发生联系起来提供了一些新线索。本研究结果还支持这样一种观点，即通过检查人体中扰动的尿液代谢物可以监测镉引起的代谢毒性，并强调了在人群水平上通过饮用水减少镉暴露的重要性。
