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.

砷是一种普遍存在的环境毒物，在全世界范围内含量很高。尽管对砷诱发的癌症进行了大量研究，但对非恶性肺部疾病机制的研究尚未完成。此外，数十年的研究主要集中在高剂量砷暴露上，这在模拟当今低剂量砷暴露的生物效应方面的用途非常有限。事实上，积累的证据表明，低剂量砷暴露（即≤100 ppb）也可能通过导致宿主对病毒感染的易感性来改变肺稳态。然而，这种改变的根本机制尚不清楚。在这项研究中，我们发现低剂量亚砷酸钠 (As (III)) 在 mRNA 和蛋白质水平上抑制主要气道粘蛋白 -MUC5AC 和 MUC5B。我们进一步证明，这种抑制不是由细胞毒性引起的，也不是由常见的粘蛋白诱导途径 - EGFR 的减少介导的。其他已建立的粘蛋白激活剂 - dsRNA、IL1β 或 IL17 无法克服 As (III) 诱导的粘蛋白抑制。有趣的是，As (III) 的抑制作用似乎是部分可逆的，并且补充所有反式视黄酸 ( t -RA) 剂量都可以依赖性地恢复粘蛋白基因表达。进一步分析表明，As (III) 处理显着降低了视黄酸受体（RARα、γ 和 RXRα）的蛋白水平以及 RARE 启动子报告活性。因此，我们的研究填补了低剂量砷暴露领域的一个重要知识空白。RA信号传导和粘蛋白基因表达的干扰可能是低剂量砷引起肺毒性的重要致病因素。