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

Chao Zhao; Hu Zhang; Jingjing Zhou; Qiwei Liu; Qiang Lu; Ying Zhang; Xiaojin Yu; Shizhi Wang; Ran Liu; Yuepu Pu; Lihong Yin

Ecotoxicology and Environmental Safety (Oct 2022)

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

Chao Zhao,
Hu Zhang,
Jingjing Zhou,
Qiwei Liu,
Qiang Lu,
Ying Zhang,
Xiaojin Yu,
Shizhi Wang,
Ran Liu,
Yuepu Pu,
Lihong Yin

Affiliations

Chao Zhao: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China; School of Nursing & School of Public Health, Yangzhou University, Yangzhou 225000, China
Hu Zhang: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Jingjing Zhou: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Qiwei Liu: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Qiang Lu: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Ying Zhang: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Xiaojin Yu: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Shizhi Wang: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Ran Liu: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Yuepu Pu: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China
Lihong Yin: School of Public Health, Southeast University, Nanjing 210009 Jiangsu, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing 210009 Jiangsu, China; Corresponding author at: School of Public Health, Southeast University, Nanjing 210009, Jiangsu, China.

Journal volume & issue: Vol. 244
p. 114071

Abstract

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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.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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