The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells

Abstract

Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-jB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-jB and/or AhR pathways remains unclear. This study was established to explore the role of NF-jB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-jB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-jB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-jB and AhR-dependent mechanism.

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

“…Pb-induced mitochondrial dysfunction may also underlie proapoptotic signaling in the exposed lung cells ( Alarifi et al, 2017 ). Activation of NF-κB and aryl hydrocarbon receptor (AhR) pathways has been considered as the potential mechanism underlying Pb-induced inflammation and toxicity in A549 lung cells ( Attafi et al, 2020 ) ( Fig. 2 ).…”

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Jin et al showed that both omeprazole and 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) inhibit the invasion of breast-cancer cells but only omeprazole inhibits the invasion of Panc1 pancreatic cancer cells [27]. Conversely, several studies have shown that AhR activation by endogenous or exogenous ligands leads to increased tumor-cell migration and aggressiveness in breast cancer [28] [29] and lung-cancer cell lines exposed to kynurenine [30] and benzo(a)pyrene (BaP) [31] [32]. Although the impact of AhR expression on carcinogenesis is difficult to characterize, its activation by diverse ligands and the role of various cofactors are important for determining how AhR influences tumor development and phenotype.…”

Dysregulation of ferroptosis may involve in the development of non‐small‐cell lung cancer in Xuanwei area

“…Among which, Cd, Cr, Ni, Cr and As, are considered to be carcinogenic for human with long‐term dusts exposure, and Cr is especially relevant for local children's risk 10 . The toxicity of Pb on lungs has been found to related to the increases in Nuclear factor kappa B (NF‐κB) and aryl hydrocarbon receptor (AHR) levels, which further lead to the increases of nitric oxide synthase (iNOS) and cytochromes of the 1 subfamily (CYP1A1) 11 . Another study shows that Cr(VI) causes alterations in DNA modification and microRNAs 12 .…”