Popcorn Flavoring Effects on Reactivity of Rat Airways in Vivo and in Vitro

Zaccone, Eric J.; Thompson, Joel A.; Ponnoth, Dovenia S.; Cumpston, Amy; Goldsmith, William T.; Jackson, Mark; Kashon, Michael L.; Frazer, David G.; Hubbs, Ann F.; Shimko, Michael J.; Fedan, Jeffrey S.

doi:10.1080/15287394.2013.796302

Cited by 26 publications

(20 citation statements)

References 44 publications

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“…In an acute inhalation toxicity mixed exposure study using ratios similar to those seen in workplaces, acetoin did not significantly alter diacetyl-induced changes in airway reactivity. 37 This provides additional support for the role of the reactive a-dicarbonyl group in diacetyl-induced toxicity and suggests the possibility that DCXR may provide a degree of protection from diacetyl-induced airway injury by removing the a-dicarbonyl group implicated in causing protein damage.…”

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confidence: 89%

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Hubbs

Fluharty

Edwards

et al. 2016

The American Journal of Pathology

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Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive a-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/ L-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this a-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the a-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease. (Am J Pathol 2016, 186: 2887e2908; http://dx

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confidence: 89%

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Hubbs

Fluharty

Edwards

et al. 2016

The American Journal of Pathology

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“…The first was to evaluate the effects of diacetyl and 2,3-pentanedione on epithelial cell ion transport following exposure to 25 ppm of flavoring vapors in vitro, in comparison to concentrations that evoke morphological damage, as well as concentrations used in our previous vivo studies (60–360 ppm; Zaccone et al, 2013). The second was to investigate the ability of intact NHBE cells to metabolize diacetyl and 2,3-pentanedione following exposure to vapors in a novel in vitro exposure system.…”

Section: Introductionmentioning

confidence: 99%

Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents

Zaccone

Goldsmith

Shimko

et al. 2015

Toxicology and Applied Pharmacology

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Inhalation of butter flavoring by workers in the microwave popcorn industry may result in “popcorn workers' lung.” In previous in vivo studies rats exposed for 6 h to vapor from the flavoring agents, diacetyl and 2,3-pentanedione, acquired flavoring concentration-dependent damage of the upper airway epithelium and airway hyporeactivity to inhaled methacholine. Because ion transport is essential for lung fluid balance, we hypothesized that alterations in ion transport may be an early manifestation of butter flavoring-induced toxicity. We developed a system to expose cultured human bronchial/tracheal epithelial cells (NHBEs) to flavoring vapors. NHBEs were exposed for 6 h to diacetyl or 2,3-pentanedione vapors (25 or ≥60 ppm) and the effects on short circuit current and transepithelial resistance (Rt) were measured. Immediately after exposure to 25 ppm both flavorings reduced Na+ transport, without affecting Cl− transport or Na+,K+-pump activity. Rt was unaffected. Na+ transport recovered 18 h after exposure. Concentrations (100–360 ppm) of diacetyl and 2,3-pentanedione reported earlier to give rise in vivo to epithelial damage, and 60 ppm, caused death of NHBEs 0 h post-exposure. Analysis of the basolateral medium indicated that NHBEs metabolize diacetyl and 2,3-pentanedione to acetoin and 2-hydroxy-3-pentanone, respectively. The results indicate that ion transport is inhibited transiently in airway epithelial cells by lower concentrations of the flavorings than those that result in morphological changes of the cells in vivo or in vitro.

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“…Current data indicate that acetoin is considerably less hazardous than diacetyl and it does not have the reactive α -dicarbonyl group, which has been implicated in the toxicity of diacetyl and 2,3-pentanedione. 40–42 …”

Section: Resultsmentioning

confidence: 99%

Pulmonary Impairment and Risk Assessment in a Diacetyl-Exposed Population

Park

Gilbert

2018

Journal of Occupational &Amp; Environmental Medicine

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Objectives: The butter flavoring additive, diacetyl (DA), can cause bronchiolitis obliterans (BO) by inhalation. A risk assessment was performed using data from a microwave popcorn manufacturing plant. Methods: Current employees’ medical history and pulmonary function tests together with air sampling over a 2.7-year period were used to analyze forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). The exposure responses for declining pulmonary function and for possible early onset of BO were estimated using multiple regression methods. Several exposure metrics were investigated; benchmark dose and excess lifetime risk of impairment were calculated. Results: Forty-six percent of the population had less than 6 months exposure to DA. Percent-of-predicted FEV1 declined with cumulative exposure (0.40 per ppm-yr, P < 10−7) as did percent FEV1/FVC (0.13 per ppm-yr, P = 0.0004). Lifetime respiratory impairment prevalence of one per thousand resulted from 0.005 ppm DA and one per thousand lifetime incidence of impairment was predicted for 0.002 ppm DA. Conclusion: DA exposures, often exceeding 1 ppm in the past, place workers at high risk of pulmonary impairment.

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Popcorn Flavoring Effects on Reactivity of Rat Airways in Vivo and in Vitro

Cited by 26 publications

References 44 publications

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents

Pulmonary Impairment and Risk Assessment in a Diacetyl-Exposed Population

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