Concentration-and time-dependent effects of benzalkonium chloride in human lung epithelial cells: Necrosis, apoptosis, or epithelial mesenchymal transition

Sou Hyun Kim, Doyoung Kwon, Seunghyun Lee, Seung Won Son, Jung Taek Kwon, Pil Je Kim, Yun Hee Lee, Young Suk Jung

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number17
JournalToxics
Volume8
Issue number1
DOIs
Publication statusPublished - 2020 Mar 1

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis
  • Chemical Health and Safety

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