Arsenic represses airway epithelial mucin expression by affecting retinoic acid signaling pathway

Yuchen Liu, Fangwei Liu, Weifeng Liang, Lingxiang Zhu, R. Clark Lantz, Jiapeng Zhu, Yin Chen

Research output: Contribution to journalArticle

Abstract

Arsenic is a ubiquitous environmental toxicant, found in high concentrations worldwide. Although abundant research has dealt with arsenic-induced cancers, studies on mechanisms of non-malignant lung diseases have not been complete. In addition, decades of research have mostly concentrated on high-dose arsenic exposure, which has very limited use in modeling the biological effects of today's low-dose exposures. Indeed, accumulated evidence has shown that low-dose arsenic exposure (i.e. ≤100 ppb) may also alter lung homeostasis by causing host susceptibility to viral infection. However, the underlying mechanism of this alteration is unknown. In this study, we found that low-dose sodium arsenite (As (III)) repressed major airway mucins-MUC5AC and MUC5B at both mRNA and protein levels. We further demonstrated that this repression was not caused by cellular toxicity or mediated by the reduction of a common mucin-inducing pathway-EGFR. Other established mucin activators- dsRNA, IL1β or IL17 were not able to override As (III)-induced mucin repression. Interestingly, the suppressing effect of As (III) appeared to be partially reversible, and supplementation of all trans retinoic acid (t-RA) doses dependently restored mucin gene expression. Further analyses indicated that As (III) treatment significantly reduced the protein level of retinoic acid receptors (RARα, γ and RXRα) as well as RARE promoter reporter activity. Therefore, our study fills in an important knowledge gap in the field of low-dose arsenic exposure. The interference of RA signaling, and mucin gene expression may be important pathogenic factors in low-dose arsenic induced lung toxicity.

Original languageEnglish (US)
Article number114959
JournalToxicology and Applied Pharmacology
Volume394
DOIs
StatePublished - May 1 2020

Keywords

  • Airway epithelial
  • Arsenic
  • Mucin
  • Retinoic acid

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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