Potential Contribution of Aromatase Inhibition to the Effects of Nicotine and Related Compounds on the Brain

Abstract

Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking and many effects of nicotine are sexually dimorphic (reviewed by Pogun and Yararbas, 2009). Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine, and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages

“…In contrast, male offspring exposed to e-cigarettes with nicotine exhibited a smaller number of gene expression changes, as well as different IPA-predicted diseases and disorders. A possible explanation for these differences observed in the male nicotine-exposed offspring is the inhibitory action of nicotine on aromatase, a required enzyme for estrogen biosynthesis that converts androgens to estrogens; lack of this enzyme results in estrogen deficiency [ 26 ]. Estrogen deficiency is known to have adverse effects in males including insufficiencies in skeletal maturation and sexual behavior [ 27 , 28 ].…”

“…, positive fold-changes in gene expression), but decreased the same processes in females (negative fold-changes in gene expression) [ 29 ]. In aromatase knock-out (ArKO) adult mice, wild-type females demonstrated depressive behaviors, while the ArKO−/− males did not [ 26 , 30 , 31 ]. Other studies using rodents have also documented that prenatal nicotine exposure increases depression and anxiety behaviors in female offspring, but not in male offspring [ 26 , 32 , 33 , 34 ].…”

Distribution of Estrogen Synthase (Aromatase) in the Human Brain

“…Basal ganglia levels are relatively low, with visibly higher levels in the ventral striatum/nucleus accumbens (Biegon et al, 2010). The regional distribution pattern is similar in adult men and women, with slightly but consistently higher levels in males (Biegon, Alia-Klein, & Fowler, 2012;Biegon et al, 2010; Figure 2). The distribution volume values derived from a two-compartment model (Gunn, Gunn, & Cunningham, 2001;Logan, 2003;Logan, Pareto, Fowler, & Biegon, 2014) in both men and women (regardless of menstrual cycle) followed the rank order: the thalamus > amygdala ¼ preoptic area > medulla (inferior olive) > cortex ¼ hippocampus, putamen, cerebellum, and white matter.…”

“…Since other promoters besides the brain-specific exon 1f (Sasano et al, 1998) are expressed in the human brain, this heterogeneity may provide the basis for brain regionspecific regulation and expression of aromatase in humans. Clearly, there is still a substantial amount of work that needs to be done to gain a more complete understanding of the regulation of human brain aromatase in health and disease and its response to common environmental and pharmacological agents (e.g., Biegon, Alia-Klein, & Fowler, 2012;Biegon et al, 2010). However, with [N-methyl-11 C]vorozole (Biegon et al, 2010;Kim et al, 2009;Lidströ m et al, 1998) and future tracers for aromatase being developed for PET studies of aromatase in the human brain (e.g., Erlandsson, Karimi, Takahashi, & Langstrom, 2007), it is now possible to perform noninvasive assessment of aromatase availability and regulation in the healthy brain and in various brain disorders and harness the results toward development of new, possibly sex-specific disease treatment or prevention strategies (de Ronde & de Jong, 2011;Gillies & McArthur, 2010).…”

Current smoking is associated with a larger waist circumference and a more androgenic profile in young healthy women from high-risk breast cancer families

“…An animal study in female baboons showed that administering nicotine at doses equivalent to that of an average smoker inhibited aromatase function by close to 50% [ 7 , 8 ]. Studies in postmenopausal women have indicated increased testosterone levels in current smokers compared with non-smokers [ 9 ].…”