Metabolic signatures for safety assessment of low-level cadmium exposure on human osteoblast-like cells

Cadmium has been widely detected in the environment and various foods. The association between cadmium burden and osteoporosis has been studied in cohorts. However, the effects and mechanisms of environmental cadmium exposure on bone metabolism is poorly understood. This study aims to investigate the altered metabolites in bone cells affected by low-level cadmium by metabolomics analysis. Specifically, we used the dosage of cadmium that do not decrease the cell viability (determined by MTT assay) to treat Saos-2 cells for 24 h. ICP-MS was applied to quantify the cadmium in culture medium and cell precipitate. The cellular metabolites were extracted and analyzed by liquid chromatography-mass spectrometry. The pathway analysis based on the identified differential metabolites showed that 1 μM cadmium significantly affected citric acid cycle and malate-aspartate shuttle, while 10 μM cadmium treatment affected citric acid cycle, alanine metabolism, glucose-alanine cycle, pyrimidine metabolism and glutamate metabolism. Taken together, 1 μM cadmium exposure could suppress the electrons transportation from the cytosol to mitochondrial matrix in Saos-2, and the impediment of the electron transport chain further inhibited downstream activities in citric acid cycle, which resulted in the accumulation of pyruvic acid. In addition, the suppressed pyrimidine degradation resulted in senescent nucleic acid accumulation and the decrease of mRNA transcription in Saos-2 cells. In general, our studies unveil the cadmium-induced metabolic perturbations in Saos-2 cells and demonstrate the feasibility of our established metabolomics pipeline to understand cadmium-induced effects on bone.