Cognition, Aryl Hydrocarbon Receptor Repressor Methylation, and Abstinence Duration-Associated Multimodal Brain Networks in Smoking and Long-Term Smoking Cessation

Abstract

Cigarette smoking and smoking cessation are associated with changes in cognition and DNA methylation; however, the neurobiological correlates of these effects have not been fully elucidated, especially in long-term cessation. Cognitive performance, percent methylation of the aryl hydrocarbon receptor repressor (AHRR) gene, and abstinence duration were used as references to supervise a multimodal fusion analysis of functional, structural, and diffusion magnetic resonance imaging (MRI) data, in order to identify associated brain networks in smokers and ex-smokers. Correlations among these networks and with smoking-related measures were performed. Cognition-, methylation-, and abstinence duration-associated networks discriminated between smokers and ex-smokers and correlated with differences in fractional amplitude of low frequency fluctuations (fALFF) values, gray matter volume (GMV), and fractional anisotropy (FA) values. Long-term smoking cessation was associated with more accurate cognitive performance, as well as lower fALFF and more GMV in the hippocampus complex. The methylation- and abstinence duration-associated networks positively correlated with smoking-related measures of abstinence duration and percent methylation, respectively, suggesting they are complementary measures. This analysis revealed structural and functional co-alterations linked to smoking abstinence and cognitive performance in brain regions including the insula, frontal gyri, and lingual gyri. Furthermore, AHRR methylation, a promising epigenetic biomarker of smoking recency, may provide an important complement to self-reported abstinence duration.

Novel DNA methylation changes in mouse lungs associated with chronic smoking

“…Our candidate gene DNAm analysis also revealed interesting patterns. Our first candidate gene, AHRR , particularly locus cg05575921, has repeatedly shown decreased DNAm in human serum [ 84 ], whole and peripheral blood [ 9 , 85 ], saliva [ 86 ], monocytes [ 87 ] and alveolar macrophages [ 10 ] of current smokers compared to never-smokers. In the same vein, even offspring exposed to CS in utero have shown altered AHRR DNAm at the same locus compared to controls [ 28 , 88–90 ].…”