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Long-term exposure to particulate matter 2.5 (PM 2.5 ) is closely related to the occurrence and development of airway inflammation. Exploration of the role of PM 2.5 in inflammation is the first step towards clarifying the harmful effects of particulate pollution. However, the molecular mechanisms underlying PM 2.5 -induced airway inflammation are yet to be fully established. In this study, we focused on the specific roles of non-coding RNAs (ncRNAs) in PM 2.5 -induced airway inflammation. In a human bronchial epithelial cell line, BEAS-2B, PM 2.5 at a concentration of 75 μg/mL induced the inflammatory response. Microarray and quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed significant upregulation of circRNA104250 and lncRNAuc001.dgp.1 during the PM 2.5 -induced inflammatory response in this cell line. Data from functional analyses further showed that both molecules promote an inflammatory response. CircRNA104250 and lncRNAuc001.dgp.1 target miR-3607-5p and affect expression of interleukin 1 receptor 1 (IL1R1), which influences the nuclear factor κB (NF-κB) signaling pathway. In summary, we have uncovered an underlying mechanism of airway inflammation by PM 2.5 involving regulation of ncRNA for the first time, which provides further insights into the toxicological effects of PM 2.5 ., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Carbon black and cadmium (Cd) are important components of atmospheric particulate matter and cigarette smoke that are closely associated with the occurrence and development of lung diseases. Carbon black, particularly carbon black nanoparticles (CBNPs), can easily adsorbs metals and cause severe lung damage and even cell death. Therefore, this study aimed to explore the mechanisms underlying the combined toxicity of CBNPs and Cd. We found that the combined exposure to CBNPs and Cd promoted significantly greater autophagosome formation and ferroptosis (increased malonaldehyde (MDA), reactive oxygen species (ROS), and divalent iron ions (Fe2+) levels and altered ferroptosis-related proteins) compared with single exposure in both 16HBE cells (human bronchial epithelioid cells) and mouse lung tissues. The levels of ferroptosis proteins, transferrin receptor protein 1 (TFRC) and glutathione peroxidase 4 (GPX4), were restored by CBNPs-Cd exposure following treatment with a 3-MA inhibitor. Additionally, under CBNPs-Cd exposure, circPSEN1 overexpression inhibited increases in the autophagy proteins microtubule-associated protein 1 light chain 3 (LC3II/I) and sequestosome-1 (P62). Moreover, increases in TFRC and Fe2+, and decreases in GPX4were inhibited. Knockdown of circPSEN1 reversed these effects. circPSEN1 interacts with autophagy-related gene 5 (ATG5) protein and upregulates nuclear receptor coactivator 4 (NCOA4), the co-interacting protein of ATG5, thereby degrading ferritin heavy chain 1 (FTH1) and increasing Fe2+ in 16HBE cells. These results indicated that the combined exposure to CBNPs and Cd promoted the binding of circPSEN1 to ATG5, thereby increasing autophagosome synthesis and ATG5-NCOA4-FTH1 axis activation, ultimately inducing autophagy-dependent ferroptosis in 16HBE cells and mouse lung tissues. This study provides novel insights into the toxic effects of CBNPs and Cd in mixed pollutants. [Display omitted] • Carbon black and cadmium co-exposure induce autophagy-dependent ferroptosis. • CircPSEN1 interacts with ATG5 protein to facilitate autophagosome formation. • CircPSEN1 activates ATG5-NCOA4-FTH1 axis leading to ferroptosis. • Ferroptosis induced by carbon black and cadmium co-exposure may be synergistic effect. [ABSTRACT FROM AUTHOR]

Benzo [a]pyrene (B [a]P) is a widespread environmental chemical pollutant that has been linked to the development of various diseases. However, the specific mechanism of action remains unclear. In this study, human bronchial epithelial 16HBE and BEAS-2B cells were exposed to B [a]P at 0–32 μM to assess the DNA-damaging effects. B [a]P exposure resulted in elevated expression of γ-H2AX, a marker of DNA damage. The m6A RNA methylation assay showed that B [a]P exposure increased the extent of m6A modification and the demethylase ALKBH5 played an integral role in this process. Moreover, the results of the comet assay and Western blot analysis showed an increase in m6A modification mediated by ALKBH5 that promoted DNA damage. Furthermore, the participation of a novel circular RNA, circ_0003552, was assessed by high-throughput sequencing under the condition of high m6A modification induced by B [a]P exposure. In subsequent functional studies, an interference/overexpression system was created to confirm that circ_0003552 participated in regulation of DNA damage. Mechanistically, circ_0003552 had an m6A binding site that could regulate its generation. This study is the first to report that B [a]P upregulated circ_0003552 through m6A modification, thereby promoting DNA damage. These findings revealed that epigenetics played a key role in environmental carcinogen-induced DNA damage, and the quantitative changes it brought might provide an early biomarker for future medical studies of genetic-related diseases and a new platform for investigations of the interaction between epigenetics and genetics. [Display omitted] • B [a]P induces DNA damage in bronchial epithelial cells. • B [a]P upregulates the degree of m6A modification by suppressing ALKBH5 expression. • Both ALKBH5 and circ_0003552 can regulate the B [a]P-induced DNA damage. • M6A modification promotes circ_0003552 production through the m6A binding site. [ABSTRACT FROM AUTHOR]

• CircRNA interact with protein to regulate the PM 2.5 -induced inflammatory responses. • Circ_406961 inhibit PM 2.5 -induced BEAS-2B cells inflammatory responses. • ILF2 affect inflammatory response via STAT3/JNK signal pathway. Fine particulate matter (PM 2.5) has been verified to augmented the incidence of pneumonia, asthma, pulmonary fibrosis, and other pulmonary diseases. Airway inflammation is the pathological basis of the respiratory system, and understanding the molecular mechanisms responsible for airway inflammation may thus support the diagnosis and treatment of respiratory diseases. In our study, human bronchial epithelial cells (BEAS-2B) were exposed to various concentrations of PM 2.5 for 48 h. PM 2.5 entered the cells, resulting in increased production of interleukin 6 (IL-6) and interleukin 8 (IL-8) and decreased the expression of circular RNA 406961 (circ_406961). Further, PM 2.5 with a concentration of 75 μg/mL was applied to mechanism study. Functional experiments further confirmed that circ_406961 inhibited PM 2.5 -induced BEAS-2B cell inflammation. RNA pull-down and mass spectrometry showed that circ_406961 interacted with interleukin enhancer-binding factor 2 (ILF2), which could regulate phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase 8 (MAPK8, JNK). Our studies showed that circ_406961 inhibited activation of STAT3/JNK pathways via interacting with ILF2 protein, thereby inhibiting the PM 2.5 -induced inflammatory reaction. [ABSTRACT FROM AUTHOR]

Long-term exposure to particulate matter 2.5 (PM 2.5) is closely related to the occurrence and development of airway inflammation. Exploration of the role of PM 2.5 in inflammation is the first step towards clarifying the harmful effects of particulate pollution. However, the molecular mechanisms underlying PM 2.5 -induced airway inflammation are yet to be fully established. In this study, we focused on the specific roles of non-coding RNAs (ncRNAs) in PM 2.5 -induced airway inflammation. In a human bronchial epithelial cell line, BEAS-2B, PM 2.5 at a concentration of 75 μg/mL induced the inflammatory response. Microarray and quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed significant upregulation of circRNA104250 and lncRNAuc001.dgp.1 during the PM 2.5 -induced inflammatory response in this cell line. Data from functional analyses further showed that both molecules promote an inflammatory response. CircRNA104250 and lncRNAuc001.dgp.1 target miR-3607-5p and affect expression of interleukin 1 receptor 1 (IL1R1), which influences the nuclear factor κB (NF-κB) signaling pathway. In summary, we have uncovered an underlying mechanism of airway inflammation by PM 2.5 involving regulation of ncRNA for the first time, which provides further insights into the toxicological effects of PM 2.5. Image 1 • CircRNA and lncRNA mediate the PM 2.5 -induced inflammatory response in BEAS-2B cells. • CircRNA and lncRNA augment PM 2.5 -induced IL-6 and IL-8 section. • CircRNA and lncRNA affect inflammatory response via NF-κB signal pathway. • CircRNA and lncRNA co-target miRNA in PM 2.5 -exposed BEAS-2B cells. Main findings of the work: CircRNA104250 and lncRNAuc001.dgp.1 promote the PM 2.5 -induced inflammatory response by co-targeting miR-3607-5p. [ABSTRACT FROM AUTHOR]

Carbon black nanoparticles (CBNPs) and cadmium (Cd) are major components of various air pollutants and cigarette smoke. Autophagy and inflammation both play critical roles in understanding the toxicity of particles and their components, as well as maintaining body homeostasis. However, the effects and mechanisms of CBNPs and Cd (CBNPs-Cd) co-exposure on the human respiratory system remain unclear. In this study, a CBNPs-Cd exposure model was constructed to explore the respiratory toxicity and combined mechanism of these chemicals on the autophagy-lysosome pathway in the context of respiratory inflammation. Co-exposure of CBNPs and Cd significantly increased the number of autophagosomes and lysosomes in human bronchial epithelial cells (16HBE) and mouse lung tissues compared to the control group, as well as the groups exposed to CBNPs and Cd alone. Autophagic markers, LC3II and P62 proteins, were up-regulated in 16HBE cells and mouse lung tissues after CBNPs-Cd co-exposure. However, treatment with Cq inhibitor (an indicator of lysosomal acid environment) resulted in a substantial decreased co-localization fluorescence of LC3 and lysosomes in the CBNPs-Cd combination group compared with the CBNPs-Cd single and control groups. No difference in LAMP1 protein expression was observed among the exposed groups. Adding 3 MA alleviated inflammatory responses, while applying the Baf-A1 inhibitor aggravated inflammation both in vitro and in vivo following CBNPs-Cd co-exposure. Factorial analysis showed no interaction between CBNPs and Cd in their effects on 16HBE cells. We demonstrated that co-exposure to CBNPs-Cd increases the synthesis of autophagosomes and regulates the acidic environment of lysosomes, thereby inhibiting autophagy-lysosome fusion and enhancing the inflammatory response in both 16HBE cells and mouse lung. These findings provide evidence for a comprehensive understanding of the interaction between CBNPs and Cd in mixed pollutants, as well as for the prevention and control of occupational exposure to these two chemicals. • CBNPs and Cd co-exposure increases inflammation in respiratory epithelial cells. • CBNPs and Cd co-exposure targets autophagosome formation and autophagy-lysosomal fusion. • CBNPs and Cd co-exposure disrupts the lysosomal acidic environment. • CBNPs and Cd co-exposure aggravates inflammation by blocking autophagic flux. [ABSTRACT FROM AUTHOR]

• B[ a ]P induces DNA damage response (DDR) in bronchial epithelial cells. • B[ a ]P upregulates circ_0057504 through suppressing DNMT3A-mediated DNA methylation. • Circ_0057504 promotes B[ a ]P-induced DDR via modulating NONO-SFPQ complex formation. Benzo[ a ]pyrene (B[ a ]P) is a class I carcinogen and hazardous environmental pollutant with genetic toxicity. Understanding the molecular mechanisms underlying genetic deterioration and epigenetic alterations induced by environmental contaminants may contribute to the early detection and prevention of cancer. However, the role and regulatory mechanisms of circular RNAs (circRNAs) in the B[ a ]P-induced DNA damage response (DDR) have not been elucidated. In this study, human bronchial epithelial cell lines (16HBE and BEAS-2B) were exposed to various concentrations of B[ a ]P, and BALB/c mice were treated with B[ a ]P intranasally. B[ a ]P exposure was found to induce DNA damage and upregulate circular RNA hsa_circ_0057504 (circ_0057504) expression in vitro and in vivo. In addition, B[ a ]P upregulated TMEM194B mRNA and circ_0057504 expression through inhibition of DNA methyltransferase 3 alpha (DNMT3A) expression in vitro. Modulation (overexpression or knockdown) of circ_0057504 expression levels using a lentiviral system in human bronchial epithelial cells revealed that circ_0057504 promoted B[ a ]P-induced DNA damage. RNA pull-down and western blot assays showed that circ_0057504 interacted with non-POU domain-containing octamer-binding (NONO) and splicing factor proline and glutamine rich (SFPQ) proteins and regulated formation of the NONO-SFPQ protein complex. Thus, our findings indicate that circ_0057504 acts as a novel regulator of DNA damage in human bronchial epithelial cells exposed to B[ a ]P. The current study reveals novel insights into the role of circRNAs in the regulation of genetic damage, and describes the effect and regulatory mechanisms of circ_0057504 on B[ a ]P genotoxicity. [ABSTRACT FROM AUTHOR]