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The health hazards of nanoparticles of neodymium oxide (NPs-Nd 2 O 3) have aroused public concern in recent years. Exposure to NPs-Nd 2 O 3 can change the level of reactive oxygen species (ROS) that cause DNA damage and alter whole transcriptome expression profiles for micro (mi)RNA, circular (circ)RNA, long noncoding (lnc)RNA, and mRNA. However, there have been no reports to our knowledge about the role of circRNAs in DNA damage caused by NPs-Nd 2 O 3. In our study, we analyzed the circRNA expression profile of human bronchial epithelial cells(16 HBE)exposed to 40 μg/ml NPs-Nd 2 O 3. Our results indicated that exposure produced 1025 up-regulated and 890 down-regulated circRNAs. Real-time quantitative polymerase chain reaction (qRT-PCR) was applied to verify some of the significantly changed circRNAs and demonstrated that circ_009773 was apparently down-regulated. Through exploration of its host gene function, we found that circ_009773 may be related to DNA damage. Functional experiments found that circ_009773 regulated NPs-Nd 2 O 3 -induced DNA damage in 16HBE cells. A circ_009773-associated competing endogenous (ce)RNA network was constructed based on one differentially expressed (DE) circRNA, 74 DE miRNAs and 208 DE mRNAs. Module analysis identified hub genes related to DNA damage and repair and a protein-protein interaction (PPI) network was created. • NPs-Nd 2 O 3 can induces cytotoxicity in 16HBE cells. • The downregulated circ_009773 promotes NPs-Nd 2 O 3 -induced DNA damage in 16HBE cells. • A competing endogenous RNA (ceRNA) network of circRNA-miRNA-mRNA was constructed in NPs-Nd 2 O 3 -induced DNA damage 16HBE cells. [ABSTRACT FROM AUTHOR]

Increasing environmental genotoxic chemicals have been shown to induce epigenetic alterations. However, the interaction between genetics and epigenetics in chemical carcinogenesis is still not fully understood. Here, we constructed an in vitro human lung carcinogenesis model (16HBE-T) by treating human bronchial epithelial cells with a typical significant carcinogen benzo(a)pyrene (BaP). We identified a novel circular RNA, circ0087385, which was overexpressed in 16HBE-T and human lung cancer cell lines, as well as in lung cancer tissues and serum exosomes from lung cancer patients. The upregulated circ0087385 after exposure to BaP promoted DNA damage in the early stage of chemical carcinogenesis and affected the cell cycle, proliferation, and apoptosis of the malignantly transformed cells. Overexpression of circ0087385 enhanced the expression of cytochrome P450 1A1 (CYP1A1), which is crucial for metabolically activating BaP. Interfering with circ0087385 or CYP1A1 reduced the levels of ultimate carcinogen benzo(a)pyrene diol epoxide (BPDE) and BPDE-DNA adducts. Interfering with CYP1A1 partially reversed the DNA damage induced by high expression of circ0087385, as well as decreased the level of BPDE and BPDE-DNA adducts. These findings provide novel insights into the interaction between epigenetics and genetics in chemical carcinogenesis which are crucial for understanding the epigenetic and genetic toxicity of chemicals. [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]

[Display omitted] Hexavalent chromium [Cr (VI)] is an important environmental pollutant and may cause lung injury when inhaled into the human body. Cr (VI) is genotoxic and can cause DNA damage, although the underlying epigenetic mechanisms remain unclear. To simulate the real-life workplace exposure to Cr (VI), we used a novel exposure dose calculation method. We evaluated the effect of Cr (VI) on DNA damage in human bronchial epithelial cells (16HBE and BEAS-2B) by calculating the equivalent real-time exposure dose of Cr (VI) (0 to 10 μM) in an environmental population. Comet experiments and olive tail moment measurements revealed increased DNA damage in cells exposed to Cr (VI). Cr (VI) treatment increased nuclear γ-H2AX foci and γ-H2AX protein expression, and caused DNA damage in the lung tissues of mice. An effective Cr (VI) dose (6 μM) was determined and used for cell treatment. Cr (VI) exposure upregulated circ_0008657, and knockdown of circ_0008657 decreased Cr (VI)-induced DNA damage, whereas circ_0008657 overexpression had the opposite effect. Mechanistically, we found that circ_0008657 binds to microRNA (miR)-203a-3p and subsequently regulates ATM serine/threonine kinase (ATM), a key protein involved in homologous recombination repair downstream of miR-203a-3p, thereby regulating DNA damage induced by Cr (VI). The present findings suggest that circ_0008657 competitively binds to miR-203a-3p to activate the ATM pathway and regulate the DNA damage response after environmental chemical exposure in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Inhalation of carbon black nanoparticles (CBNPs) can impair lung tissue and cause DNA damage, but the epigenetic mechanism responsible for these effects is still unclear. We explored the role of circular RNAs (circRNAs) in DNA damage induced by CBNPs in the lung. Human bronchial epithelial cell lines (16HBE and BEAS-2B) were treated with 0, 5, 10, 20, 40, or 80 μg/ml CBNPs for 24, 48, and 72 h, and BALB/c mice were exposed to 8 and 80 μg/d CBNPs for 14 days to establish in vitro and vivo models of CBNP exposure, respectively. We found that CBNPs caused DNA double-strand breaks in the lung. Using high-throughput sequencing and quantitative real-time PCR to identify CBNP-related circRNAs, we identified a novel circRNA (circ_0089282) that was overexpressed in the CBNP-exposed group. We used gain-/loss-of-function approaches, RNA pulldown assays, and silver staining to explore the regulatory function of circ_0089282 and its interactions with targeted proteins. We found that circ_0089282 interference could increase CBNP-induced DNA damage, whereas overexpression resulted in the opposite. Circ_0089282 could directly bind to the fused in sarcoma (FUS) protein and positively regulate downstream DNA repair protein DNA ligase 4 (LIG4) through FUS. This regulatory effect of circRNA on DNA damage via promotion of LIG4 illustrated the interactions between genetics and epigenetics in toxicology. [ABSTRACT FROM AUTHOR]

Background: Lung cancer has high morbidity and mortality worldwide with non-small cell lung cancer (NSCLC) accounting for 85% of the cases. Therapies for lung cancer have relatively poor outcomes and further improvements are required. Circular RNAs have been reported to participate in the occurrence and progression of cancer. Information on the functions and mechanism of circRNAs in lung cancer is limited and needs more exploration. Methods: We detected expression of genes and proteins by qPCR and western blot. Function of circSATB2 was investigated using RNA interference and overexpression assays. Location of circSATB2 was assessed by fluorescence in situ hybridization (FISH). Interaction of circSATB2, miR-326 and FSCN1 was confirmed by dual-luciferase reporter assay. Results: Data from the investigation showed that circSATB2 was highly expressed in NSCLC cells and tissues. circSATB2 positively regulated fascin homolog 1, actin-bundling protein 1 (FSCN1) expression via miR-326 in lung cancer cells. Furthermore, circSATB2 can be transferred by exosomes and promote the proliferation, migration and invasion of NSCLC cells, as well as induce abnormal proliferation in normal human bronchial epithelial cells. Also, circSATB2 was highly expressed in serumal exosomes from lung cancer patients with high sensitivity and specificity for clinical detection and was related to lung cancer metastasis. Conclusions: circSATB2 participated in the progression of NSCLC and was differentially expressed in lung cancer tissue and serumal exosomes. circSATB2 may be potential biomarker for the diagnosis of NSCLC. [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]

Exposure to high concentrations of copper is associated with pulmonary inflammation and chronic respiratory disease (CRD). Epigenetic modulation of noncoding RNAs contributes to the development of several CRDs. It is unknown whether epigenetic modulation is involved in copper mediated pulmonary inflammation and CRD. We conducted a case-control study of 101 CRD cases and 161 control subjects in Shijiazhuang, China, and evaluated circRNAs and cytokine levels (IL-6 and IL-8) by qPCR and ELISA. Urinary copper concentration was determined by inductively coupled plasma mass spectrometry. Linear mixed models and generalized linear mixed models were used to assess the associations of circRNAs with CRD, urinary copper, and cytokines. We exposed the human bronchial epithelial cell line, 16HBE, to copper and assessed the functional role of a circRNA, circ_0008882, by RNA overexpression. Cellular location of circ_0008882 was assessed by separation of nuclear and cytoplasmic RNAs. Nine circRNAs were associated with an increased risk for CRDs, while the relative expression of circ_0008882 was decreased after copper exposure in vitro and in vivo. Copper exposure stimulated 16HBE cells to release proinflammatory IL-6 and IL-8. The release of the cytokines was inhibited by overexpression of circ_0008882. These results suggest a role for circ_0008882 in the regulation of CRD associated inflammation following copper exposure. [Display omitted] • Circular RNA, circ_0008882, is related to chronic respiratory disease. • Expression of circ_0008882 decreases after copper exposure in vitro and in vivo. • IL-6 and IL-8, induced by copper, are inhibited by overexpression of circ_0008882. [ABSTRACT FROM AUTHOR]

circNOL10 is a circular RNA expressed at low levels in lung cancer, though its functions in lung cancer remain unknown. Here, the function and molecular mechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co‐regulated by methylation of its parental gene Pre‐NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1). circNOL10 promotes the expression of transcription factor sex comb on midleg‐like 1 (SCML1) by inhibiting transcription factor ubiquitination and thus also affects regulation of the humanin (HN) polypeptide family by SCML1. circNOL10 also affects mitochondrial function through regulating the humanin polypeptide family and affecting multiple signaling pathways, ultimately inhibiting cell proliferation and cell cycle progression, and promoting the apoptosis of lung cancer cells, thereby inhibiting lung cancer development. This study investigates the functions and molecular mechanisms of circNOL10 in the development of lung cancer and reveals its involvement in the transcriptional regulation of the HN polypeptide family by SCML1. The results also demonstrate the inhibitory effect of HN on lung cancer cells growth. These findings may identify novel targets for the molecular therapy of lung cancer. This study provides new evidence for the molecular mechanism whereby circRNAs may affect transcriptional regulation in lung cancer cells, and also reveals that circNOL10 inhibits lung cancer development by promoting SCLM1‐mediated transcriptional regulation of the humanin (HN) polypeptide family. The results also demonstrate the inhibitory effect of HN on lung cancer growth. [ABSTRACT FROM AUTHOR]