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

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

doi:10.3389/fnmol.2022.800406

Abstract

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.

Highlights

The use of electronic nicotine delivery systems (ENDS), known as electronic cigarettes (e-cigarettes) has been dramatically increasing in recent years, and it has become a serious public health issue
Menthol is one of the most prevalent and common flavors used in e-cigarettes; so, we compared the behavioral responses in vapor-exposed mice between the nicotine alone group and nicotine group mixed with menthol flavoring
Mean cotinine levels averaged from multiple mice per exposure run on the random days were higher in urine from the mice exposed to vapors of nicotine alone (319.3 ± 33.99 ng/mL) or nicotine with menthol flavor (452.8 ± 92.71 ng/mL) compared to the Veh control (50.97 ± 13.36 ng/mL) [F(2,6) = 12.65, p = 0.0070, Supplementary Figure 1]

Summary

Introduction

The use of electronic nicotine delivery systems (ENDS), known as electronic cigarettes (e-cigarettes) has been dramatically increasing in recent years, and it has become a serious public health issue. The popularity of e-cigarette use continues to increase, research evidence based on scientific knowledge is lacking and the main focused aspect of e-cigarettes include their beneficial roles in tobacco smoking cessation or reduction, their health risks, and their environmental consequences (Rom et al, 2015; HartmannBoyce et al, 2020). A recent increase in the prevalence of e-cigarettes among young adults and adolescents may largely be due to their widely available flavors which appeal to the youth (Ambrose et al, 2015; Villanti et al, 2017; Cullen et al, 2019a,b). The incorporated effects of flavorings when added in the nicotine-containing vapor and the underlying mechanisms are largely unknown

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