Abstract

Heavy metals and Brominated diphenyl ether flame-retardants (BDEs) often coexist in the environment and are capable of inducing injury, cytotoxicity or genotoxicity in human epithelial cells of the lung. We studied the effects of single Cadmium chloride (CdCl2) or CdCl2/BDE (47 or 209) mixtures in airway epithelial cells, using A549 cell line cultured at submerged conditions and air–liquid interface (ALI) (an in vitro model described as physiologically relevant in vivo-like). We evaluated cell viability, oxidative stress, apoptosis, DNA damage/repair (Comet assay, γH2AX phosphorylation ser139), mitochondrial redox balance (NOX-4, Nrf2 and TFAM) and cell barrier integrity (TEER, ZO-1, Claudin-1, E-cadherin-1) in A549 cells exposed to CdCl2 (1 nM to 10 µM), or to CdCl2 (100 nM)/BDEs (47 or 209) (100 nM). CdCl2 (10 μM) reduced cell viability and increased apoptosis. CdCl2 (100 nM) significantly affected DNA-damage/repair (Olive Tail length production), γH2AX phosphorylation and oxidative stress (ROS/JC-1 production) in submerged cell cultures. CdCl2 (100 nM) decreased viability, TEER, ZO-1, Claudin-1 and E-cadherin-1 mRNA expression, and Nrf2 and TFAM while increased NOX-4, in ALI culture of cells. In both cell culture approaches, the cells stimulated with Cadmium/BDEs mixtures did not show a significant increase in the effects observed in the cells treated with CdCl2 alone. CdCl2 inhalation might exert cytotoxicity and genotoxicity, playing a pivotal role in the uncontrolled oxidative stress, damaging DNA and gene expression in airway epithelial cells. No additional or synergistic adverse effects of CdCl2/BDEs mixture were observed in comparison to CdCl2 alone in lung epithelium.

Highlights

  • Heavy metals such as cadmium (Cd) and the flame retardant known as brominated diphenyl ethers (BDEs) are toxic air pollutants ranked on the Priority List of Hazardous Substances [1] (WHO Regional Office for Europe, 2015; 2019 Substance Priority List)

  • We described the effect of CdCl2 and CdCl2/BDE mixtures in an “in vitro” model of A549 cell line obtained using: (1) submerged cell culture to study cell viability, oxidative stress, apoptosis and DNA damage in epithelial cells cultured in monolayer and (2) 3D air–liquid interface (ALI) cell culture to evaluate cell viability, oxidative stress (NOX-4), redox balance (NOX-4, nuclear factor erythroid 2–related factor 2 (Nrf2) and transcription factor A mitochondrial (TFAM)) and barrier integrity (TEER, and ZO-1, Claudin-1 and E-cadherin mRNA expression) in stratified epithelial cells

  • We observed that CdCl2 or CdCl2/BDE mixtures affected the increase in NADPH oxidase 4 (NOX-4) and downregulated Nrf2 and TFAM expression, without any additional effect. These findings suggest that CdCl2 might be involved in mitochondrial bioenergetics and biogenesis of NOX-4 reactive oxygen species (ROS)-dependent activities, repressing Nrf2 and TFAM endogenous antioxidant responses to cell stress of the stratified epithelium of the airways exposed to environmental pollution

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Summary

Introduction

Heavy metals such as cadmium (Cd) and the flame retardant known as brominated diphenyl ethers (BDEs) are toxic air pollutants ranked on the Priority List of Hazardous Substances [1] (WHO Regional Office for Europe, 2015; 2019 Substance Priority List). Heavy metals are released into the environment after the burning of coal, diesel fuel, gasoline and other fossil fuels or to the incineration of municipal waste and to the polluting metal alloy and electroplating facilities. They are added to various materials such as electronic equipment, plastics, carpet liners and textiles [2,3]. The coexistence of Cd and BDE in the environment and biological systems poses a substantial risk to human health, but their potential joint toxicities remain so far elusive [7]. The pollutant mixtures represent more real environmental conditions, and to study their combined toxicity is a more accurate manner to describe the effect of environmental contamination on human health

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