Biological changes in C57BL/6 mice following 3 weeks of inhalation exposure to cigarette smoke or e-vapor aerosols

Lee, K. Monica; Hoeng, Julia; Harbo, Sam J.; Kogel, Ulrike; Gardner, William; Oldham, Michael J.; Benson, Eric M.; Talikka, Marja; Kondylis, Athanasios; Martin, Florian; Titz, Bjoern; Ansari, Sam; Trivedi, Keyur; Guedj, Emmanuel; Elamin, Ashraf; Ivanov, Nikolai V.; Vanscheeuwijck, Patrick; Peitsch, Manuel C.; McKinney, William T.

doi:10.1080/08958378.2019.1576807

Cited by 29 publications

(41 citation statements)

References 38 publications

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“…Both nicotine dependent and nicotine independent effects were found. Although most studies found significant effects of vaping, two industry funded studies did not,103105 consistent with the previously mentioned relation between industry funding and observed effects of vaping 6…”

Section: Animal Studiessupporting

confidence: 82%

What are the respiratory effects of e-cigarettes?

Gotts

Jordt

McConnell

et al. 2019

BMJ

392

303

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Electronic cigarettes (e-cigarettes) are alternative, non-combustible tobacco products that generate an inhalable aerosol containing nicotine, flavors, propylene glycol, and vegetable glycerin. Vaping is now a multibillion dollar industry that appeals to current smokers, former smokers, and young people who have never smoked. E-cigarettes reached the market without either extensive preclinical toxicology testing or long term safety trials that would be required of conventional therapeutics or medical devices. Their effectiveness as a smoking cessation intervention, their impact at a population level, and whether they are less harmful than combustible tobacco products are highly controversial. Here, we review the evidence on the effects of e-cigarettes on respiratory health. Studies show measurable adverse biologic effects on organ and cellular health in humans, in animals, and in vitro. The effects of e-cigarettes have similarities to and important differences from those of cigarettes. Decades of chronic smoking are needed for development of lung diseases such as lung cancer or chronic obstructive pulmonary disease, so the population effects of e-cigarette use may not be apparent until the middle of this century. We conclude that current knowledge of these effects is insufficient to determine whether the respiratory health effects of e-cigarette are less than those of combustible tobacco products.

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Section: Animal Studiessupporting

confidence: 82%

What are the respiratory effects of e-cigarettes?

Gotts

Jordt

McConnell

et al. 2019

BMJ

392

303

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“…In contrast, the Test Red group showed minimal changes in the cellular perturbation network, as previously observed in a shorter (3-week) study. 31 Similarly, in a 90-day nose-only inhalation study in which rats were exposed to PG/VG mixtures, with and without nicotine, 34 showed only limited gene expression changes in the lungs.…”

Section: Discussionmentioning

confidence: 99%

“…These NPA values from all applied network models were aggregated to generate a BIF to assess the overall impact of exposure on biology of the lungs. 31 This causal biological network approach, based on transcriptomics data from the lung, showed the highest impact (expressed as BIF) in the 3R4F CS group at all timepoints ( Figure 6(d)), whereas the relative biological impact factors (RBIFs-relative to the CS at month 7, BIF set as 100%) for the Test Red group remained close to baseline, indicating a significantly lower impact of e-vapor aerosol exposure. A weak but significant impact was observed in the Cessation and Switching groups at months 4 and 7 (Figure 6(d)).…”

Section: Transcriptomics and Proteomicsmentioning

confidence: 91%

“…The inhalation atmosphere ( Supplementary Table S4) was well-controlled over 7 months of exposure and the results were overall comparable to prior studies. 31 For the 3R4F CS exposure, the overall mean TPM concentration was 540 mg/L (within 2% of the target concentration of 550 mg/L TPM), with a % relative standard deviation (RSD) of 3%. For Test Red e-vapor aerosol exposures, the mean TPM was 1091 mg/L (within 1% of the target concentration of 1100 mg/L TPM), with a % RSD of 3%.…”

Section: Exposure Characterizationmentioning

confidence: 94%

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A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products

Kumar

Kogel

Talikka

et al. 2021

Toxicology Research and Application

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Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.

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“…As seen in a previous e-vapor aerosol inhalation study in mice by Lee et al, the amplitude of e-vapor effects was much lower than the effects after cigarette smoke (3R4F) exposure. 42 Although the PG/W 6-hour exposure group was anticipated to show a similar pattern and higher impact in the network perturbations, this was not the case. The 1-hour and 3-hour groups did show an increase in the number of networks perturbed and, based on the BIF value, the underlying pathway mechanisms were partially shared.…”

Section: Discussionmentioning

confidence: 98%

Thirteen-week nose-only inhalation exposures of propylene glycol aerosols in Sprague Dawley rats with a lung systems toxicology analysis

Langston

Randazzo

Kogel

et al. 2021

Toxicology Research and Application

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The objectives of this study were to increase PG exposure above concentrations tested by Suber et al. and use systems toxicology analysis of lung tissue to understand molecular events. Sprague Dawley rats were exposed to filtered air (sham), propylene glycol/water (PG/W; 90:10) or a propylene glycol/vegetable glycerin/water (PG/VG/W; 50:40:10) reference. The reference group was added at the high dose to observe any changes that might be associated with a carrier more in line with e-vapor products. Macroscopic examinations and terminal organ weights revealed no observations associated with exposure to PG/W or reference. Food consumption and body weights were unaffected by PG/W or reference when compared to sham. No exposure related alterations were observed in serum chemistry, hematology, coagulation, urinalysis or BALF cytology and clinical chemistry. Although clinical observations of dried red material around the nose in the high dose PG/W group were reported, histopathology showed no nasal hemorrhaging which was previously reported by Suber et al. Non-adverse PG/W and reference related findings of minimal mucous cell hyperplasia were noted in nasal cavity section II. No other exposure-related findings were noted in the primary or recovery necropsies. A systems toxicology analysis on lung tissue showed no statistically significant differentially expressed transcripts or proteins compared to the sham group. The endpoints measured from the PG/W high dose group did not differ significantly from those in the more common carrier PG/VG/W. As anticipated, exposure to PG aerosols was slightly irritating but well tolerated. Accordingly, the highest PG exposure (5 mg/L, 6 hrs/day) was regarded as the NOAEC, corresponding to a PG delivered dose of 1,152 mg/kg/day in rats.

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Biological changes in C57BL/6 mice following 3 weeks of inhalation exposure to cigarette smoke or e-vapor aerosols

Cited by 29 publications

References 38 publications

What are the respiratory effects of e-cigarettes?

What are the respiratory effects of e-cigarettes?

A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products

Thirteen-week nose-only inhalation exposures of propylene glycol aerosols in Sprague Dawley rats with a lung systems toxicology analysis

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