Metabolome-wide association study suggests antagonistic responses to cadmium and selenium in diseased human lungs

Abstract

Background and Aim: Cadmium (Cd) is a toxic environmental metal that binds selenium (Se) and contributes to many lung diseases. Humans have widespread exposures to Cd through diet and cigarette smoking, and studies in rodent models show that Se can protect against Cd toxicities. We performed metabolome-wide association study (MWAS) of Cd and Se in diseased and non-diseased human lungs to test for possible Cd-Se interactions. Methods: We analyzed tissue from 31 human lung explants, including 25 from patients with end-stage lung diseases, including idiopathic pulmonary fibrosis, cystic fibrosis, and chronic obstructive lung disease (COPD)/emphysema. We used ICP-MS (Inductively Coupled Plasma Mass Spectrometry) to measure Cd and Se, and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to conduct metabolomics analysis. Results: Metabolic pathway associations with Cd were similar to those previously observed in experimental models, including amino acid, lipid and energy-related pathways, many of which were also associated with Se. Two-way hierarchical cluster analysis (HCA) of metabolites associated with Cd revealed separation of individuals according to disease, with COPD/emphysema in the highest Cd cluster, and non-diseased individuals in the lowest Cd cluster. HCA of Se-associated metabolites revealed that COPD/emphysema also clustered by lower Se compared to others. More pathway associations occurred for the ratio of Cd:Se than either Cd or Se alone, suggesting an antagonistic relationship, and network analysis showed that most metabolites were associated with either Cd or Se. A relatively small number of polyunsaturated fatty acids and metabolites associated with inflammatory signaling had high Eigenvector centrality scores, suggesting a central mechanism of antagonistic interaction. Conclusions: Overall, the data show that metabolic pathway responses in human lung vary with Cd:Se ratio in a pattern suggesting that Se is antagonistic to Cd toxicity. Keyword: Human lung disease, environmental metals, metabolic disruption, high-resolution metabolomics.