CeO 2 nanoparticles (NPs) have been shown to cause lung fibrosis, however, the exact underlying molecular mechanisms are poorly understood. In this study, we have conducted a mass spectrometry-based global metabolomic analysis of human bronchial epithelial BEAS-2B cells treated by CeO 2 NPs with different aspect ratios and assessed their toxicity on the bronchial epithelial cells by various cell-based functional assays. Although CeO 2 NPs at doses ranging from 12.5 μg/mL to 25 μg/mL displayed low cytotoxicity on the bronchial epithelial cells, the metabolomic analysis revealed a number of metabolites in the cellular metabolic pathways of sphingosine-1-phosphate, fatty acid oxidation, inflammation, etc . were significantly altered by CeO 2 NPs, especially those with high aspect ratios. More importantly, the robustness of metabolomics findings was further successfully validated in mouse models upon acute and chronic exposures to CeO 2 NPs. Mechanistically, CeO 2 NPs upregulated transforming growth factor beta-1 (TGF-β1) levels in BEAS-2B cells in an aspect ratio-dependent manner through enhancing the expression of early growth response protein 1 (EGR-1). In addition, both in vitro and in vivo studies demonstrated that CeO 2 NPs significantly induced the expression of sphingosine kinase 1 (SHPK1), phosphorylated Smad2/3 and lung fibrosis markers. Moreover, targeting SPHK1, TGFβ receptor or Smad3 phosphorylation significantly attenuated the fibrosis-promoting effects of CeO 2 NPs, and SPHK1-S1P pathway exerted a greater effect on the TGF-β1-mediated lung fibrosis compared to the conventional Smad2/3 pathway. Collectively, our studies have identified the metabolomic changes in BEAS-2B cells exposed to CeO 2 NPs with different aspect ratios and revealed the subtle changes in metabolic activities that traditional approaches might have missed. More importantly, we have discovered a previously unknown molecular mechanism underlying CeO 2 NP-induced lung fibrosis with different aspect ratios, shedding new insights on the environmental hazard potential of CeO 2 NPs.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- mass spectrometry
- oxide nanoparticles
- poor prognosis
- oxidative stress
- fatty acid
- endothelial cells
- single cell
- liver failure
- drug induced
- pulmonary fibrosis
- risk assessment
- high throughput
- hepatitis b virus
- intensive care unit
- tyrosine kinase
- liquid chromatography
- diabetic rats
- high resolution
- respiratory failure
- nitric oxide
- walled carbon nanotubes