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Open AccessArticle

Concentration- and Time-Dependent Effects of Benzalkonium Chloride in Human Lung Epithelial Cells: Necrosis, Apoptosis, or Epithelial Mesenchymal Transition

1
Lab of Molecular Toxicology, College of Pharmacy, Pusan National University, Busan 46241, Korea
2
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA
3
Risk Assessment Division, Environmental Health Research Department, National Institute of Environmental Research, Incheon 22689, Korea
4
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Toxics 2020, 8(1), 17; https://doi.org/10.3390/toxics8010017
Received: 12 January 2020 / Revised: 20 February 2020 / Accepted: 21 February 2020 / Published: 2 March 2020
(This article belongs to the Section Toxicology and Public Health)
Benzalkonium chloride (BAC), an antimicrobial agent in inhalable medications and household sprays, has been reported to be toxic to pulmonary organs. Although cell membrane damage has been considered as the main cytotoxic mechanism of BAC, its concentration- and time-dependent cellular effects on lung epithelium have not been fully understood. In the present study, human lung epithelial (H358) cells were exposed to 0.2–40 μg/mL of BAC for 30 min or 21 days. Cell membranes were rapidly disrupted by 30 min exposure, but 24 h incubation of BAC (4–40 μg/mL) predominantly caused apoptosis rather than necrosis. BAC (2–4 μg/mL) induced mitochondrial depolarization, which may be associated with increased expression of pro-apoptotic proteins (caspase-3, PARP, Bax, p53, and p21), and decreased levels of the anti-apoptotic protein Bcl-2. The protein expression levels of IRE1α, BiP, CHOP, and p-JNK were also elevated by BAC (2–4 μg/mL) suggesting the possible involvement of endoplasmic reticulum stress in inducing apoptosis. Long-term (7–21 days) incubation with BAC (0.2–0.6 μg/mL) did not affect cell viability but led to epithelial-mesenchymal transition (EMT) as shown by the decrease of E-cadherin and the increase of N-cadherin, fibronectin, and vimentin, caused by the upregulation of EMT transcription factors, such as Snail, Slug, Twist1, Zeb1, and Zeb2. Therefore, we conclude that apoptosis could be an important mechanism of acute BAC cytotoxicity in lung epithelial cells, and chronic exposure to BAC even at sub-lethal doses can promote pulmonary EMT. View Full-Text
Keywords: benzalkonium chloride; lung epithelial cells; cytotoxicity; endoplasmic reticulum stress; epithelial–mesenchymal transition benzalkonium chloride; lung epithelial cells; cytotoxicity; endoplasmic reticulum stress; epithelial–mesenchymal transition
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Kim, S.H.; Kwon, D.; Lee, S.; Son, S.W.; Kwon, J.-T.; Kim, P.-J.; Lee, Y.-H.; Jung, Y.-S. Concentration- and Time-Dependent Effects of Benzalkonium Chloride in Human Lung Epithelial Cells: Necrosis, Apoptosis, or Epithelial Mesenchymal Transition. Toxics 2020, 8, 17.

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