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Modification of the Peripheral Olfactory System by Electronic Cigarettes

Abdullah AlMatrouk, Kayla Lemons, Tatsuya Ogura, Weihong Lin

10.1002/cphy.c210007

Source: Volume 11, Issue 4, October 2021

Published online: October 2021

Full Article on Wiley Online Library



Abstract

Electronic cigarettes (e‐cigs) are used by millions of adolescents and adults worldwide. Commercial e‐liquids typically contain flavorants, propylene glycol, and vegetable glycerin with or without nicotine. These chemical constituents are detected and evaluated by chemosensory systems to guide and modulate vaping behavior and product choices of e‐cig users. The flavorants in e‐liquids are marketing tools. They evoke sensory percepts of appealing flavors through activation of chemical sensory systems to promote the initiation and sustained use of e‐cigs. The vast majority of flavorants in e‐liquids are volatile odorants, and as such, the olfactory system plays a dominant role in perceiving these molecules that enter the nasal cavity either orthonasally or retronasally during vaping. In addition to flavorants, e‐cig aerosol contains a variety of by‐products generated through heating the e‐liquids, including odorous irritants, toxicants, and heavy metals. These harmful substances can directly and adversely impact the main olfactory epithelium (MOE). In this article, we first discuss the olfactory contribution to e‐cig flavor perception. We then provide information on MOE cell types and their major functions in olfaction and epithelial maintenance. Olfactory detection of flavorants, nicotine, and odorous irritants and toxicants are also discussed. Finally, we discuss the cumulated data on modification of the MOE by flavorant exposure and toxicological impacts of formaldehyde, acrolein, and heavy metals. Together, the information presented in this overview may provide insight into how e‐cig exposure may modify the olfactory system and adversely impact human health through the alteration of the chemosensory factor driving e‐cig use behavior and product selections. © 2021 American Physiological Society. Compr Physiol 11:2621‐2644, 2021.

Figure 1. Figure 1. Chemical compounds in electronic cigarette (e‐cig) aerosol and routes to stimulate the main olfactory epithelium (MOE). Aerosol of e‐cig contains flavorants, nicotine, PG/VG, and thermal decomposition by‐products, such as formaldehyde and heavy metals (Cd, As, and Pb). These chemicals enter the nasal cavity and stimulate olfactory sensory epithelium through either the orthonasal (via the nostril, blue arrow) or the retronasal (through the mouse and back of the throat, pink arrow) route. The olfactory sensory epithelium houses olfactory sensory neurons. They detect flavorants and odorous irritants and toxicants in the aerosol and send sensory signals to the olfactory bulb which is the first brain station processing olfactory information. The output signals from the olfactory bulb are sent to other brain regions for further processing that gives rise to sensory perceptions of smell and flavor, and other cognitive functions including memory, reward, fear, and anxiety.
Figure 2. Figure 2. Peripheral olfactory sensory organs and OSN axonal targeting. (A) Internal structure of a mouse heminose, showing peripheral olfactory sensory organs and tissues: MOE, main olfactory epithelium (light blue area); GG, Grüeneberg ganglion; SO, the septal organ of Masera; and VNO, vomeronasal organ. MOB, main olfactory bulb. A, anterior; P, posterior; D, dorsal; V, ventral. (B) OSNs in the MOE project their axons to the MOB. Axon terminals of mature OSNs make synapses to the dendrites of output neuron mitral/tufted cells and interneurons (not shown) in the glomerulus. Individual OSNs in the drawing are color coded, indicating that they express only one type of OR. Axons of OSNs expressing the same OR converge and terminate at the same glomerulus. Modified, with permission, from Ogura T, et al., 2011 187 and drawing of Dr. Aaron Sathyanesan.
Figure 3. Figure 3. The main olfactory epithelium. (A) Image of a coronal section of a mouse olfactory turbinate, where main olfactory epithelium (MOE) lines on the surface of the nasal turbinate. Modified, with permission, from Dunston D, et al., 2013 56 . The cell layer structure of the MOE (blue box) is shown as an illustration in (B). (B) Illustration of cell types present in the main olfactory epithelium (MOE). The MOE is a pseudostratified structure made up primarily of OSNs, including both mature and immature OSNs, supporting cells (or sustentacular cells), basal cells, microvillous cells (MCs), and Bowman's glands (not shown). The schematic shows only the apically located transient receptor potential M5 (TRPM5)‐expressing MCs (TRPM5‐MCs). Courtesy of Dr. Aaron Sathyanesan.
Figure 4. Figure 4. Morphology of mature OSNs and the canonical olfactory signal transduction pathway. (A) Illustration of a mature OSN. The bipolar OSN has its apical dendrite reaching the MOE surface and its basal axon projecting to the olfactory bulb. The apical end of the dendrite forms a knob, from which 10 to 15 cilia emanate and extend into the mucus layer. Odor detection takes place at the cilia membrane where odor receptors (ORs) and the components of the signaling pathway are located. The olfactory signal transduction mechanism at the cilia membrane (blue box) is illustrated in (B). (B) The canonical olfactory signal transduction pathway. Odorants bind to an OR, which is coupled to a G‐protein which consists of G αolf , G β , and G γ subunits. Activated Gα olf then stimulates adenylate cyclase III (ACIII) to generate cAMP, which opens cyclic nucleotide‐gated (CNG) channel, resulting in membrane depolarization by Ca 2+ and Na + influx. Increased Ca 2+ opens Ca 2+ ‐activated Cl − channel (ANO2), resulting in further depolarization and generation of action potentials. In some ONSs, Ca 2+ also activates TRPM5 channel (not shown in the drawing). Modified from Dr. Aaron Sathyanesan.
Figure 5. Figure 5. Cholinergic TRPM5‐expressing microvillous cells and cholinergic regulation in response to xenobiotics in the MOE. (A) GFP‐expressing microvillous cells imaged from a strip of MOE from a ChAT (BAC) ‐eGFP mouse. (B) Confocal image from a MOE section of a ChAT (BAC) ‐eGFP mouse labeled with an antibody against the neuronal marker PGP 9.5 to visualize olfactory sensory neurons (OSNs) (red). Note that the ChAT (GFP)‐expressing microvillous cells are not labeled by the PGP 9.5 antibody and are located in the superficial layer, which consists primarily of cell bodies of supporting cells. (C, D): Individual GFP‐expressing microvillous cells from ChAT (BAC) ‐eGFP and TRPM5‐GFP mice, respectively. An antibody against GFP was used to enhance the GFP signal at the apical microvilli. (E) Confocal image of TRPM5‐GFP‐expressing microvillous cell is overlaid with the image of immunoreactivity against vesicular ACh transporter (VAChT) antibody (red). The GFP fluorescence and VAChT immunoreactivity (red) are colocalized as shown in yellow. (F) Image of TRPM5 (GFP)‐expressing microvillous cell immunoreacted to an antibody against espin for labeling microvilli (red). Scales: A = 50 μm, B = 20 μm, C–F = 5 μm. Modified, with permission, from Ogura T, et al., 2011 187 . (G) Schematic illustration of a potential network of cholinergic regulation in the MOE. TRPM5‐MCs respond to xenobiotic stimulation and release ACh, which activates the surrounding supporting cells via M3‐ACh receptor and also suppresses OSN responsivity via M2/M4‐ACh receptors. Activated supporting cells metabolize or biotransform xenobiotics via enzymatic reactions. Suppressed OSN responsivity protects the cells from excess Ca 2+ load due to overreaction to high levels of odorous irritants. Panel G is a schematic model based on the data from Ogura T, et al., 2011 187 ; Lemons K, et al., 2020, 134,135 ; Fu Z, et al., 2018 72 ; AlMatrouk et al., 2018 3 .
Figure 6. Figure 6. Modification of the olfactory sensitivity by e‐cig exposure and potential behavior and health consequences. The olfactory sensory neurons detect both flavorants and nicotine. Flavorants in e‐cig induce satisfactory sensation which makes e‐cig products appealing. The olfactory sensitivity is quickly reduced by aerosol exposure during vaping and after repetitive stimulation due to sensory adaptation. To compensate for the reduced satisfaction or enjoyment associated with the decrease in olfactory sensitivity, users may seek more vaping exposure and/or select e‐liquids with strong flavors or switch to other products for compensation. The excess vaping and strong flavorants may over stimulate the olfactory sensory neurons and be toxic to the MOE which further reduces olfactory sensitivity due to additional toxic effects, which may also lead to olfactory dysfunction. To mask the harsh or irritating sensation, users may prefer e‐liquids containing soothing flavors such as menthol and mint.


Figure 1. Chemical compounds in electronic cigarette (e‐cig) aerosol and routes to stimulate the main olfactory epithelium (MOE). Aerosol of e‐cig contains flavorants, nicotine, PG/VG, and thermal decomposition by‐products, such as formaldehyde and heavy metals (Cd, As, and Pb). These chemicals enter the nasal cavity and stimulate olfactory sensory epithelium through either the orthonasal (via the nostril, blue arrow) or the retronasal (through the mouse and back of the throat, pink arrow) route. The olfactory sensory epithelium houses olfactory sensory neurons. They detect flavorants and odorous irritants and toxicants in the aerosol and send sensory signals to the olfactory bulb which is the first brain station processing olfactory information. The output signals from the olfactory bulb are sent to other brain regions for further processing that gives rise to sensory perceptions of smell and flavor, and other cognitive functions including memory, reward, fear, and anxiety.


Figure 2. Peripheral olfactory sensory organs and OSN axonal targeting. (A) Internal structure of a mouse heminose, showing peripheral olfactory sensory organs and tissues: MOE, main olfactory epithelium (light blue area); GG, Grüeneberg ganglion; SO, the septal organ of Masera; and VNO, vomeronasal organ. MOB, main olfactory bulb. A, anterior; P, posterior; D, dorsal; V, ventral. (B) OSNs in the MOE project their axons to the MOB. Axon terminals of mature OSNs make synapses to the dendrites of output neuron mitral/tufted cells and interneurons (not shown) in the glomerulus. Individual OSNs in the drawing are color coded, indicating that they express only one type of OR. Axons of OSNs expressing the same OR converge and terminate at the same glomerulus. Modified, with permission, from Ogura T, et al., 2011 187 and drawing of Dr. Aaron Sathyanesan.


Figure 3. The main olfactory epithelium. (A) Image of a coronal section of a mouse olfactory turbinate, where main olfactory epithelium (MOE) lines on the surface of the nasal turbinate. Modified, with permission, from Dunston D, et al., 2013 56 . The cell layer structure of the MOE (blue box) is shown as an illustration in (B). (B) Illustration of cell types present in the main olfactory epithelium (MOE). The MOE is a pseudostratified structure made up primarily of OSNs, including both mature and immature OSNs, supporting cells (or sustentacular cells), basal cells, microvillous cells (MCs), and Bowman's glands (not shown). The schematic shows only the apically located transient receptor potential M5 (TRPM5)‐expressing MCs (TRPM5‐MCs). Courtesy of Dr. Aaron Sathyanesan.


Figure 4. Morphology of mature OSNs and the canonical olfactory signal transduction pathway. (A) Illustration of a mature OSN. The bipolar OSN has its apical dendrite reaching the MOE surface and its basal axon projecting to the olfactory bulb. The apical end of the dendrite forms a knob, from which 10 to 15 cilia emanate and extend into the mucus layer. Odor detection takes place at the cilia membrane where odor receptors (ORs) and the components of the signaling pathway are located. The olfactory signal transduction mechanism at the cilia membrane (blue box) is illustrated in (B). (B) The canonical olfactory signal transduction pathway. Odorants bind to an OR, which is coupled to a G‐protein which consists of G αolf , G β , and G γ subunits. Activated Gα olf then stimulates adenylate cyclase III (ACIII) to generate cAMP, which opens cyclic nucleotide‐gated (CNG) channel, resulting in membrane depolarization by Ca 2+ and Na + influx. Increased Ca 2+ opens Ca 2+ ‐activated Cl − channel (ANO2), resulting in further depolarization and generation of action potentials. In some ONSs, Ca 2+ also activates TRPM5 channel (not shown in the drawing). Modified from Dr. Aaron Sathyanesan.


Figure 5. Cholinergic TRPM5‐expressing microvillous cells and cholinergic regulation in response to xenobiotics in the MOE. (A) GFP‐expressing microvillous cells imaged from a strip of MOE from a ChAT (BAC) ‐eGFP mouse. (B) Confocal image from a MOE section of a ChAT (BAC) ‐eGFP mouse labeled with an antibody against the neuronal marker PGP 9.5 to visualize olfactory sensory neurons (OSNs) (red). Note that the ChAT (GFP)‐expressing microvillous cells are not labeled by the PGP 9.5 antibody and are located in the superficial layer, which consists primarily of cell bodies of supporting cells. (C, D): Individual GFP‐expressing microvillous cells from ChAT (BAC) ‐eGFP and TRPM5‐GFP mice, respectively. An antibody against GFP was used to enhance the GFP signal at the apical microvilli. (E) Confocal image of TRPM5‐GFP‐expressing microvillous cell is overlaid with the image of immunoreactivity against vesicular ACh transporter (VAChT) antibody (red). The GFP fluorescence and VAChT immunoreactivity (red) are colocalized as shown in yellow. (F) Image of TRPM5 (GFP)‐expressing microvillous cell immunoreacted to an antibody against espin for labeling microvilli (red). Scales: A = 50 μm, B = 20 μm, C–F = 5 μm. Modified, with permission, from Ogura T, et al., 2011 187 . (G) Schematic illustration of a potential network of cholinergic regulation in the MOE. TRPM5‐MCs respond to xenobiotic stimulation and release ACh, which activates the surrounding supporting cells via M3‐ACh receptor and also suppresses OSN responsivity via M2/M4‐ACh receptors. Activated supporting cells metabolize or biotransform xenobiotics via enzymatic reactions. Suppressed OSN responsivity protects the cells from excess Ca 2+ load due to overreaction to high levels of odorous irritants. Panel G is a schematic model based on the data from Ogura T, et al., 2011 187 ; Lemons K, et al., 2020, 134,135 ; Fu Z, et al., 2018 72 ; AlMatrouk et al., 2018 3 .


Figure 6. Modification of the olfactory sensitivity by e‐cig exposure and potential behavior and health consequences. The olfactory sensory neurons detect both flavorants and nicotine. Flavorants in e‐cig induce satisfactory sensation which makes e‐cig products appealing. The olfactory sensitivity is quickly reduced by aerosol exposure during vaping and after repetitive stimulation due to sensory adaptation. To compensate for the reduced satisfaction or enjoyment associated with the decrease in olfactory sensitivity, users may seek more vaping exposure and/or select e‐liquids with strong flavors or switch to other products for compensation. The excess vaping and strong flavorants may over stimulate the olfactory sensory neurons and be toxic to the MOE which further reduces olfactory sensitivity due to additional toxic effects, which may also lead to olfactory dysfunction. To mask the harsh or irritating sensation, users may prefer e‐liquids containing soothing flavors such as menthol and mint.
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Article Title: Modification of the Peripheral Olfactory System by Electronic Cigarettes
 

How to Cite

Abdullah AlMatrouk, Kayla Lemons, Tatsuya Ogura, Weihong Lin. Modification of the Peripheral Olfactory System by Electronic Cigarettes. Compr Physiol 2021, 11: 2621-2644. doi: 10.1002/cphy.c210007