Menthol Flavor in E-Cigarette Vapor Modulates Social Behavior Correlated With Central and Peripheral Changes of Immunometabolic Signalings

Zhibin Xu, Ye Tian, A. Xiang Li, Jiahang Tang, Xiao Yuan Jing, Chunshan Deng, Zhizhun Mo, Jiaxuan Wang, Juan Lai, Xuemei Liu, Xuantong Guo, Tao Li, Shupeng Li, Liping Wang, Zhonghua Lu, Zuxin Chen, Xin An Liu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The use of electronic cigarette (e-cigarette) has been increasing dramatically worldwide. More than 8,000 flavors of e-cigarettes are currently marketed and menthol is one of the most popular flavor additives in the electronic nicotine delivery systems (ENDS). There is a controversy over the roles of e-cigarettes in social behavior, and little is known about the potential impacts of flavorings in the ENDS. In our study, we aimed to investigate the effects of menthol flavor in ENDS on the social behavior of long-term vapor-exposed mice with a daily intake limit, and the underlying immunometabolic changes in the central and peripheral systems. We found that the addition of menthol flavor in nicotine vapor enhanced the social activity compared with the nicotine alone. The dramatically reduced activation of cellular energy measured by adenosine 5′ monophosphate-activated protein kinase (AMPK) signaling in the hippocampus were observed after the chronic exposure of menthol-flavored ENDS. Multiple sera cytokines including C5, TIMP-1, and CXCL13 were decreased accordingly as per their peripheral immunometabolic responses to menthol flavor in the nicotine vapor. The serum level of C5 was positively correlated with the alteration activity of the AMPK-ERK signaling in the hippocampus. Our current findings provide evidence for the enhancement of menthol flavor in ENDS on social functioning, which is correlated with the central and peripheral immunometabolic disruptions; this raises the vigilance of the cautious addition of various flavorings in e-cigarettes and the urgency of further investigations on the complex interplay and health effects of flavoring additives with nicotine in e-cigarettes.

Original languageEnglish
Article number800406
JournalFrontiers in Molecular Neuroscience
StatePublished - 10 Mar 2022
Externally publishedYes


  • e-cigarette
  • electronic nicotine delivery systems (ENDS)
  • menthol
  • nicotine
  • social activity


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