(P02-025-23) Inverse Association of Selenium With Cadmium in Non-Diseased and Diseased Human Lungs

Objectives: This study used non-diseased and diseased human lungs to begin translation from mice to humans the finding that increased essential nutrient metal selenium (Se) protects against lung toxicity and pathology caused by the environmental metal cadmium (Cd).

Methods: Non-diseased cadaver lungs and diseased (including idiopathic pulmonary fibrosis, IPF; chronic obstructive pulmonary disease, COPD, and other diseases) lungs were used. Western blot analysis was used to test for abundance of Zip8, a Fe, Zn and Mn transporter that also transports both Cd and Se (as selenite) and related transporter Zip14. Cd and Se were measured by ICP-MS. Metabolomics was performed by high-resolution mass spectrometry. Integrated metallome-metabolome analysis used xMWAS and pathway enrichment analysis used mummichog..

Results: Zip8 and Zip14 were higher in human IPF lungs (n=8) compared to non-disease lungs (n=5) (p < 0.05). Cd content was higher in IPF lungs and COPD lungs (p < 0.05). Both IPF and COPD lungs had lower Se content than non-diseased lungs (p < 0.05). Pathway enrichment analysis with Cd showed associations (p < 0.05) with amino acid, lipid and energy-related pathways, considerably overlapping with those found for Cd-treated mice. Pathways associated with Se in human lungs overlapped with these pathways. More pathway associations occurred for the ratio of Cd to Se (Cd/Se) than either Cd or Se alone, and most associated individual metabolites had opposite direction of association with Cd and Se. Oxidized polyunsaturated fatty acids involved in inflammatory signaling were increased and had high centrality in metabolic networks associated with Cd/Se ratio.

Conclusions: Major transporters for Cd and Se are increased in abundance in IPF lungs. Despite this, Cd and Se varied in opposite directions in association with disease, suggesting that these metals compete on Zip8 and other transporters and that Cd has higher affinity than Se. Metabolic pathway associations with Cd and Se in human lung are similar to those found in mouse lung, and increased oxidized lipids with Cd/Se ratio is consistent with enhanced inflammation and impaired antioxidant selenoenzyme activities.

Funding Sources: NIEHS R21 ES031824, R01 ES031980, R01 ES032189, P30 ES019776, R01 ES032189 and F32 ES033908, NIDDK RC2 DK118619, and Georgia CTSA UL1TR002378.