Short-term respiratory cadmium exposure causes pulmonary function decline accompanied by upregulation of sphingolipid synthesis in mouse lungs.

Cadmium (Cd) is a respiratory toxicant. Previous reports have confirmed that chronic respiratory Cd exposure causes chronic obstructive pulmonary disease-like lesions in a murine model. This study aimed to evaluate the influence of short-term Cd exposure on lung function. Adult C57BL/6J mice were exposed to Cd through inhaling different concentrations of cadmium chloride aerosols (25 mg/L or 100 mg/L, 2 h per day) for 5 days. Serum Cd was quantified by ICP-MS. Lung histopathology and lung function were evaluated. Pulmonary inflammatory cytokines were measured by real-time RT-PCR. Untargeted metabolomics, transcriptome sequencing, and targeted lipidomics were used to explore the mechanism. Serum Cd level was slightly elevated and alveolar structure was mildly damaged in Cd-exposed mice. An obvious lung function decline was observed, accompanied by upregulation of inflammatory cytokines in Cd-exposed mouse lungs. Untargeted metabolomics and transcriptomics showed that pulmonary lipid metabolism was disrupted in Cd-exposed mice. Lipidomics confirmed that sphingolipids, including ceramides and sphingosine, were significantly increased in Cd-exposed mouse lungs. Pulmonary SPTLC1, an essential subunit of the rate-limiting enzyme for ceramide de novo synthesis, and ceramide synthases, such as CerS2 and CerS6, were elevated in Cd-exposed mice. The present results provide experimental data that short-term environmental exposure causes pulmonary function decline probably by upregulating pulmonary sphingolipid synthesis.