Selenium supplementation prevents metabolic and transcriptomic responses to cadmium in mouse lung

Abstract Background The protective effect of selenium (Se) on cadmium (Cd) toxicity is well documented, but underlying mechanisms are unclear. Methods Male mice fed standard diet were given Cd (CdCl 2 , 18 μmol/L) in drinking water with or without Se (Na 2 SeO 4, 20 μmol/L) for 16 weeks. Lungs were analyzed for Cd concentration, transcriptomics and metabolomics. Data were analyzed with biostatistics, bioinformatics, pathway enrichment analysis, and combined transcriptome-metabolome-wide association study. Results Mice treated with Cd had higher lung Cd content (1.7 ± 0.4 pmol/mg protein) than control mice (0.8 ± 0.3 pmol/mg protein) or mice treated with Cd and Se (0.4 ± 0.1 pmol/mg protein). Gene set enrichment analysis of transcriptomics data showed that Se prevented Cd effects on inflammatory and myogenesis genes and diminished Cd effects on several other pathways. Similarly, Se prevented Cd-disrupted metabolic pathways in amino acid metabolism and urea cycle. Integrated transcriptome and metabolome network analysis showed that Cd treatment had a network structure with fewer gene-metabolite clusters compared to control. Centrality measurements showed that Se counteracted changes in a group of Cd-responsive genes including Zdhhc11 , (protein-cysteine S-palmitoyltransferase), Ighg1 (immunoglobulin heavy constant gamma-1) and associated changes in metabolite concentrations. Conclusion Co-administration of Se with Cd prevented Cd increase in lung and prevented Cd-associated pathway and network responses of the transcriptome and metabolome. Se protection against Cd toxicity in lung involves complex systems responses. General significance Environmental Cd stimulates proinflammatory and profibrotic signaling. The present results indicate that dietary or supplemental Se could be useful to mitigate Cd toxicity.