Lipid metabolism disorders contribute to hepatotoxicity of ICR mice induced by nitrosamines exposure

• Published in: Environment international 2022-09, Vol.167, p.107423-107423, Article 107423
• Main Authors: Zhang, Hu, Lu, Lu, Zhao, Chao, Liu, Qiwei, Zhou, Qian, Zhang, Ying, Pu, Yuepu, Wang, Shizhi, Liu, Ran, Yin, Lihong
• Format: Article
• Language: English
• Subjects: beta oxidation; ceramides; cytokines; diacylglycerols; edema; environment; Fatty acid oxidation; fatty acid transport proteins; fatty acids; Hepatotoxicity; homeostasis; Lipidomics; liver; Mice; N-nitrosamines; nitrosamines; Oxidative stress; phosphatidylcholines; phosphatidylethanolamines; triacylglycerols
• ISSN: 0160-4120; 1873-6750
• DOI: 10.1016/j.envint.2022.107423

[Display omitted] •Nitrosamines exposure induced hepatotoxicity in the liver of mice.•Lipid metabolism disorders associated with hepatotoxicity caused by nitrosamines.•Nitrosamines induced fatty acid oxidation correlated with inflammation in the liver.•CD36-mediated fatty acid oxidation related to the enhancement of oxidative stress. Health risks caused by crucial environmental carcinogens N-nitrosamines triggered ubiquitous attention. As the liver exerted vital function through metabolic process, lipid metabolism disorders have been confirmed as potential drivers for toxicological effects, and the mechanisms of lipid regulation related to hepatotoxicity induced by N-nitrosamines remained largely unclear. In this study, we comprehensively explored the disturbance of hepatic lipid homeostasis in mice induced by nitrosamines. The results implied that nitrosamines exposure induced hepatotoxicity accompanied by liver injury, inflammatory infiltration, and hepatic edema. Lipidomics profiling analysis indicated the decreased levels of phosphatidic acids (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), lyso-phosphatidylcholines (LPC), lyso-phosphatidylethanolamines (LPE), diacylglycerols (DAG) and triacylglycerols (TAG), the elevation of ceramides (Cer) and decomposition of free fatty acids (FFA) in high-dose nitrosamines exposure group. Importantly, nitrosamines exposure promoted fatty acid oxidation (FAO) by facilitating fatty acid uptake and decomposition, together with the upregulation of genes associated with FAO accompanied by the activation of inflammatory cytokines TNF-α, IL-1β and NLRP3. Furthermore, fatty acid translocase CD36-mediated fatty acid oxidation was correlated with the enhancement of oxidative stress in the liver caused by nitrosamines exposure. Overall, our results contributed to the new strategies to interpret the early toxic effects of nitrosamines exposure.