Cadmium perturbed metabolomic signature in pancreatic beta cells correlates with disturbed metabolite profile in human urine.

Abstract

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.