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Cell-Specific Toxicity of Short-Term JUUL Aerosol Exposure to Human

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Cell-Specific Toxicity of Short-Term JUUL Aerosol Exposure to Human Pinkston et al. Respir Res (2020) 21:269 https://doi.org/10.1186/s12931-020-01539-1 RESEARCH Open Access Cell-specifc toxicity of short-term JUUL aerosol exposure to human bronchial epithelial cells and murine macrophages exposed at the air–liquid interface Rakeysha Pinkston1,2, Hasan Zaman2, Ekhtear Hossain2, Arthur L. Penn2 and Alexandra Noël2* Abstract Backgroud: JUUL, an electronic nicotine delivery system (ENDS), which frst appeared on the US market in 2015, controled more than 75% of the US ENDS sales in 2018. JUUL-type devices are currently the most commonly used form of ENDS among youth in the US. In contrast to free-base nicotine contained in cigarettes and other ENDS, JUUL contains high levels of nicotine salt (35 or 59 mg/mL), whose cellular and molecular efects on lung cells are largely unknown. In the present study, we evaluated the in vitro toxicity of JUUL crème brûlée-favored aerosols on 2 types of human bronchial epithelial cell lines (BEAS-2B, H292) and a murine macrophage cell line (RAW 264.7). Methods: Human lung epithelial cells and murine macrophages were exposed to JUUL crème brûlée-favored aerosols at the air–liquid interface (ALI) for 1-h followed by a 24-h recovery period. Membrane integrity, cytotoxicity, extracellular release of nitrogen species and reactive oxygen species, cellular morphology and gene expression were assessed. Results: Crème brûlée-favored aerosol contained elevated concentrations of benzoic acid (86.9 μg/puf), a well- established respiratory irritant. In BEAS-2B cells, crème brûlée-favored aerosol decreased cell viability ( 50%) and increased nitric oxide (NO) production ( 30%), as well as iNOS gene expression. Crème brûlée-favored≥ aerosol did not afect the viability of either H292 cells≥ or RAW macrophages, but increased the production of reactive oxygen species (ROS) by 20% in both cell types. While crème brûlée-favored aerosol did not alter NO levels in H292 cells, RAW macrophages≥ exposed to crème brûlée-favored aerosol displayed decreased NO ( 50%) and down-regulation of the iNOS gene, possibly due to increased ROS. Additionally, crème brûlée-favored aerosol≥ dysregulated the expression of several genes related to biotransformation, infammation and airway remodeling, including CYP1A1, IL-6, and MMP12 in all 3 cell lines. Conclusion: Our results indicate that crème brûlée-favored aerosol causes cell-specifc toxicity to lung cells. This study contributes to providing scientifc evidence towards regulation of nicotine salt-based products. Keywords: JUUL, Electronic nicotine delivery system (ENDS), Electronic-cigarettes, Vaping, Air–liquid interface (ALI) Background *Correspondence: [email protected] Since their entry into the US market in 2007, electronic 2 Department of Comparative Biomedical Sciences, School of Veterinary nicotine delivery system (ENDS) devices, popularly Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton called electronic-cigarettes (e-cigs), have lowered Rouge, LA 70803, USA Full list of author information is available at the end of the article the incidence of active tobacco smoking [1]. Te © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pinkston et al. Respir Res (2020) 21:269 Page 2 of 15 battery-operated ENDS devices, designed to deliver [21]. It also was recently reported that 15–17 year- an inhalable heated aerosolized mixture of nicotine, olds are 16 times more likely than adults between the favoring compounds, and humectants [propylene glycol ages of 25–34 years to use JUUL [22]. Tis increases (PG) and vegetable glycerin (VG)] are marketed as, and the possibility that teenage JUUL users will develop a believed by many to be, a safer alternative to cigarette life-long addiction to nicotine, and switch to a more smoking [2]. E-cig devices were formally targeted to complex e-cig product or even turn to traditional tobacco adult smokers attempting to quit smoking; however, products [1, 2]. If continued use of JUUL or other e-cig e-cigs have quickly gained immense popularity among devices were shown to cause long-term respiratory adolescents and young adults, making these devices efects, widespread e-cig and JUUL usage among teens the most popular form of tobacco product usage within and young adults would become a major public health this demographic [1]. Moreover, ENDS products are concern [1, 23, 24]. more attractive to youth (< 18 years of age) compared Humectants and favoring additives used in e-liquids to cigarettes at least in part due to targeted marketing are “generally regarded as safe” (GRAS) in food and and availability of a substantial assortment of favored cosmetic items [25]; however, the safety of favoring e-liquids [3–6]. According to the Centers for Disease additives when inhaled has not been thoroughly Control and Prevention (CDC), e-cig usage among youth established [26]. For instance, several studies showed that has increased to more than 5 million individuals in the the cytotoxic efects of ENDS products are linked to the US as of 2019 [7, 8], in addition to about 8 million adult presence of multiple favoring chemicals [26–31]. Indeed, users [9]. Tis striking increase in ENDS usage among favoring chemicals have been reported to cause lung youth and young adults has been suggested to be due in toxicity and respiratory conditions, including asthma, large part to the popularity of JUUL devices [10]. when inhaled, thus posing a potential threat to the JUUL is a leading e-cig brand in the US, and in 2018, respiratory health of users [32–34]. Common favoring controlled more than 70% of the e-cig market shares. agents in e-liquids include aldehydes, such as vanillin, Even though JUUL only began to be marketed in 2015, and alcohols, such as ethyl maltol, which have been in 2018 it was the most popular brand used among pre- identifed in JUUL pod favored liquids, including crème teens, teens and young adults [11]. Te concentration brûlée and mango [31, 35, 36]. Tese chemicals have and form of nicotine could be one reason for the been shown to be cytotoxic, cause respiratory irritation popularity of JUUL compared to other e-cig brands. [30, 31, 35], and reduced lung function [37]. Flavoring Te JUUL device, similar in size and shape to a memory additives chemically react with humectants (PG/VG) stick, is uniquely designed to utilize disposable pods to form aldehyde acetals (e.g., vanillin PG/VG acetal), containing e-liquids consisting of benzoic acid and high which activate pro-infammatory respiratory irritant levels of nicotine in the form of nicotine salts, labeled as receptors [38, 39]. Moreover, these favoring chemicals 3% or 5% of nicotine (35 or 59 mg/mL) [12]. Te latter transfer from the liquid phase to the aerosol phase at pod liquid concentration is equivalent to the nicotine a 39–79% efciency rate [31, 35]. Vanillin PG acetal content of 1 full pack of fltered unburned cigarettes and vanillin VG acetals also were identifed in JUUL (10–15 mg nicotine/unburned cigarette; 1–2 mg nicotine crème brûlée pod liquids and transferred to the aerosol absorbed) [13, 14]. JUUL pod’s liquid composition allows at a rate of about 68% (0.8 ± 0.04 mg/puf) and 59% the nicotine salts to be heated at lower temperatures (7.9 ± 0.8 mg/puf), respectively [35]. In addition to the compared to other ENDS devices (e.g. 3rd generation formation of harmful acetals, humectants, when heated e-cig device), which allows high levels of nicotine to be by an ENDS device, have been shown to form toxic inhaled more easily, with minimized discomfort and carbonyl compounds [40–45], some of which, including optimal absorption [15–20]. Tis gives rise to a transfer formaldehyde, are carcinogenic and have been suggested of both freebase nicotine and the constituent acid (in to play a role in several respiratory diseases commonly this case benzoic acid) to the JUUL user [12, 15–17], seen in cigarette smokers [45, 46]. Another concern is in contrast to other types of e-cigs that use “freebase that base ingredients of e-cig liquids (PG, VG) could be nicotine” at lower concentrations (3–36 mg/mL) [18], respiratory irritants and be harmful to the lungs, leading because high freebase concentrations can provide an to airway obstruction and infammation [47, 48]. While unpleasant feeling to the throat and lungs [1, 19, 20]. benzoic acid is often used as a food preservative, in Many young ENDS users do not realize that the inhalable form, it is a well-known respiratory irritant that majority of e-cig products contain nicotine. A recent can cause coughing and sore throat if exposure continues study, published in BMJ’s Tobacco Control journal, found [49]. Further, heated and aerosolized e-liquid from any that although many young users are aware of JUUL, they ENDS device can produce fne and ultrafne particles that are not necessarily aware of the high nicotine content contain polyaromatic hydrocarbons, carbonyls, aldehydes Pinkston et al.
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