Metabolomic transition trajectory and potential mechanisms of N-nitrosomethylbenzylamine induced esophageal squamous cell carcinoma in rats

• Published in: Ecotoxicology and environmental safety Vol. 244; p. 114071
• Main Authors: Zhao, Chao, Zhang, Hu, Zhou, Jingjing, Liu, Qiwei, Lu, Qiang, Zhang, Ying, Yu, Xiaojin, Wang, Shizhi, Liu, Ran, Pu, Yuepu, Yin, Lihong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2022; Elsevier
• Subjects: Esophageal squamous cell carcinoma (ESCC); Immune suppression; Inflammation; Metabolomic transition; Nitrosomethylbenzylamine (NMBA); Metabolomic transition; Immune suppression; Nitrosomethylbenzylamine (NMBA); Inflammation; Esophageal squamous cell carcinoma (ESCC)
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.114071

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC. •NMBA-induced ESCC model was constructed in F344 rats.•The serum metabolic transition trajectory in the process of ESCC was depicted.•Perturbations of NAD+ biosynthesis were critical for the carcinogenesis of NMBA.•IDO1-KYN-AHR axis in tryptophan metabolism was activated by NMBA.•SPHK1-S1P-S1PR1 axis in sphingolipid metabolism was provoked by NMBA.