Dysregulation of fatty acid metabolism associated with esophageal inflammation of ICR mice induced by nitrosamines exposure

Abstract

Nitrosamines, as ubiquitous environmental carcinogens with adverse impact on human health, were crucial inducers of esophageal cancer (EC). Esophageal inflammation (EI) was an important biological process and considered to be associated with the progression of EC. However, the underlying regulatory mechanism of EI process caused by nitrosamines exposure remained largely unclear. In this study, a metabolomics approach based on mass spectrometry was utilized to explore the effect of nitrosamines exposure to ICR mice. Also, the changes of pivotal metabolic enzyme levels, urinary nitrosamines and histopathological analysis were evaluated. The results showed that nitrosamines exposure was intimately interrelated with EI process in mice. Metabolomics profiling analysis indicated that nitrosamines caused significant alterations of metabolic pathway predominantly enriched in fatty acid metabolism. Targeted metabolomics analysis revealed that nitrosamines promoted decomposition of fatty acids and facilitated fatty acid β-oxidation (FAO) of mice. The significant increase of carnitine palmitoyltransferase 1 (CPT1) and downregulation of acetyl-CoA acyltransferase 2 (ACAA2) would promote FAO in EI process induced by nitrosamines. Additionally, the exposure levels of more than half of nitrosamines in urine were correlated with inflammatory fatty acid biomarkers. Overall, this study found that EI triggered by nitrosamines may be associated with the promotion of FAO, and provided novel insights for evaluating the underlying mechanism of environmental pollutant-caused toxicity based on metabolomics.