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Occupational silica exposure caused a serious disease burden of silicosis. There is currently a lack of sensitive and effective biomarkers for silicosis, and the pathogenesis of silicosis is unclear. Exosomes were significant in the pathogenesis of silicosis, and our study was carried out from exosomal proteomics and cytokine analysis. Firstly, the plasma levels of cytokines were detected using a Luminex multiplex assay, and the results indicated that the plasma levels of TNF-α, IL-6, CCL2, CXCL10, and PDGF-AB were significantly higher in silicosis patients than in silica-exposed workers and controls (p < 0.05). After correlation analysis, the plasma levels of cytokines were positively correlated with exosomal protein concentration. Secondly, data-independent acquisition (DIA) was performed on plasma-derived exosomes in the screening population, which identified 88, 151, 293, and 53 differentially expressed proteins (DEPs) in exposure/control, silicosis/control, silicosis/exposure, and silicosis stage Ⅲ/silicosis stage Ⅰ groups respectively. After parallel reaction monitoring (PRM) in an independent verification population, the results indicated that the changing trend of 15 DEPs was coincident in screening and verification results. The result of correlation analysis indicated that the plasma level of TNF-α was negatively correlated with the expression of exosomal DSP, KRT78, SERPINB12, and CALML5. The AUC of combined determination of TNF-α and CALML5 reached 0.900, with a sensitivity of 0.714 and a specificity of 0.933. Overall, our study revealed the exosomal proteomic profiling of silicosis patients, silica-exposed workers, and controls, indicating that exosomes were significant in the pathogenesis of silicosis. It also revealed that the combined of the plasma levels of cytokines and the expression of exosomal DEPs could increase determination efficiency. This study provided directions for the development of silicosis biomarkers and a scientific basis for the pathogenesis research of silicosis in the future. [Display omitted] • The plasma cytokine levels were correlated with exosomal protein concentrations. • The exosomal proteomic profiling was revealed in silicosis patients and controls. • The plasma level of TNF-α was correlated with the expression of exosomal CALML5. • The combination of TNF-α and exosomal CALML5 had good determination efficiency. [ABSTRACT FROM AUTHOR]

Abstract Occupational exposure to Cr (VI) can cause DNA damage, genetic instability and elevate the risk of cancer. Here we investigated Cr (VI)-induced DNA damage and 8-oxoguanine DNA glycosylase 1 (hOGG1) gene expression in electroplating workers. The hOGG1 gene encodes a DNA repair enzyme that is crucial in DNA oxidation damage repair. Deficiency in hOGG1 DNA repair capacity contributes to the accumulation of DNA damage and genetic instability. To address the issues, we collected peripheral blood samples and urine samples from 162 electroplating workers and 84 control subjects. We measured blood chromium levels, urine chromium levels, DNA damage, and hOGG1 mRNA expression. We found significantly higher levels of blood chromium, urine chromium, and DNA damage in electroplating workers compared with controls, whereas mRNA levels of the hOGG1 gene were significantly lower in the exposed workers. Furthermore, in electroplating workers we found that blood Cr had a positive association with DNA damage as measured with the tail DNA%. Meanwhile, tail DNA% was positively associated with hOGG1 mRNA expression. Finally, the effect of potassium dichromate treatment was investigated in a human B lymphoblastoid cell line (LCL). We observed that potassium dichromate induced a concentration-dependent decrease in hOGG1 mRNA. After removing the K 2 Cr 2 O 7 -containing medium for 3 days and 7 days, the abundance of hOGG1 mRNA expression recovered to a similar level as the controls. Collectively, our findings suggest that decreased hOGG1 mRNA expression in occupationally exposed populations partially contribute to Cr (VI) induced DNA damage. Graphical abstract Image 1 Highlights • Occupational exposure to Cr (VI) was associated with increased levels of DNA damage and decreased levels of hOGG1 expression. • There was a positive correlation between blood Cr concentration and DNA damage in electroplating workers. • Treatment of cells with Cr (VI) led to an initial down-regulation of the hOGG1 gene mRNA. • Decreased hOGG1 mRNA expression in occupationally exposed populations partially contribute to Cr (VI) induced DNA damage. [ABSTRACT FROM AUTHOR]

Abstract Man-made mineral fibres (MMMFs) such as glass wool (GW), rock wool (RW) and refractory ceramic fibres (RCFs) are widely used as substitutes of asbestos. The present study aimed to investigate the cytotoxic effects on human bronchial epithelial cells (BEAS-2B) exposed to GW1, RW1 and RCF2, considering their properties similar to that of asbestos. We assessed cell viability; cell morphological changes; apoptotic rate; DNA damage; reactive oxygen species (ROS) generation; activities of caspase-3, caspase-8 and caspase-9; and expression levels of FasL, phosphorylated p38, and total p38 MAPK proteins. N -acetyl- l -cysteine (NAC) was used as an ROS scavenger. We observed that MMMFs, especially RCF2, evidently changed cellular morphology, promoted DNA damage, and induced apoptosis. In addition, the cytotoxicities of MMMFs were dependent on ROS generation, and NAC could decrease their toxicity. Furthermore, our results showed that apoptosis induced by MMMFs was mediated by the mitochondrial apoptotic pathway and Fas death receptor pathway. Moreover, the p38 MAPK signalling pathway was also involved in the cytotoxicities of MMMFs. NAC exerts a protective effect against apoptosis and DNA damage induced by GW1, RW1 and RCF2. This study provides important implications for understanding the potential toxic effects of GW1, RW1 and RCF2 exposure; it also indicates that NAC may prevent respiratory diseases induced by exposure to MMMFs. Highlights • MMMFs evidently changed cell morphology, promoted DNA damage, and induced apoptosis, especially for RCF2. • MMMFs induced cytotoxicity of BEAS-2B and NAC has the protective effect. • The mitochondrial apoptotic pathway and Fas death receptor pathway involved in apoptosis induced by MMMFs. • p38 MAPK signal pathway was also involved in the cytotoxicities of MMMFs. [ABSTRACT FROM AUTHOR]

The carcinogenicity of hexavalent chromium [Cr(VI)] and its compounds has been widely recognized, yet the mechanism of genetic damage is still not fully understood. The ribosomal DNA (rDNA) copy number is recently considered a potential marker of cancer-associated stress. To investigate the roles of rDNA copy number variation (CNV) in DNA damage responses (DDRs) induced by Cr(VI) and the potential mechanism from nucleolar protein HRAS, a cross-sectional study in Cr(Ⅵ)-exposed workers and an in vitro experiment using HeLa cells were conducted. Our results showed increased levels of rDNA CNV, DDRs, and HRAS expression in Cr(VI)-exposed workers. Generalized linear regression analyses showed that Cr(VI) exposure was significantly positively associated with increased levels of rDNA CNV, DDRs, and HRAS expression in Cr(VI)-exposed workers. Moreover, there were pairwise associations between rDNA CNV, DDRs, and HRAS levels. Mediation analyses found that rDNA CNV significantly mediated the association between Cr(VI) exposure and DDRs. The in vitro experiments further confirmed that Cr(VI) treatment induced increased levels of rDNA CNV, DDRs, and HRAS expression in HeLa cells. Cr(VI)-induced rDNA CNV, ATM activation, and apoptosis damage were then strongly enhanced by HRAS depletion with siRNA in vitro , suggesting the important role of HRAS in CNV and DDRs caused by Cr(VI). The combined results of the human and cell line studies indicated that Cr(VI) exposure might enhance rDNA CNV by regulation of HRAS expression, which leads to Cr(VI)-induced genetic damage. [Display omitted] • Cr(VI) enhanced rDNA copy numbers, DNA damage responses, and HRAS expression. • The DNA copy number variation mediated Cr(VI)-induced DNA damage responses. • HRAS was associated with DNA copy number variation and DNA damage responses. • HRAS depletion enhanced Cr(VI)-induced rDNA amplification and DNA damage responses. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cr (VI) exposure caused miRNAs dysregulation in vitro and in electroplating workers. • DNA damage response was associated with one or more miRNAs expression. • Functional study revealed differentially expressed miRNAs might play roles in DDR. We aimed to explore the expression of miRNAs and their potential roles in the DNA damage response (DDR) induced by Cr (VI) exposure in human B lymphoblast cells (HMy2.CIR cells) and in a population of Cr (VI)-exposed humans. Methods: Differentially expressed miRNAs were found by a combination of miRNA sequencing and RT-qPCR validation in HMy2.CIR cells treated with K 2 Cr 2 O 7. Differentially expressed miRNAs related to DDR were selected for functional study. The expression levels of differential miRNAs were also investigated in chromate workers. Results: A total of 214 differentially expressed miRNAs were identified by sequencing, and the expression of 5 miRNAs among 25 associated with DDR was found to be consistent between sequencing and validation studies. Functional studies showed that miR-148a-3p, miR-21-5p, and miR-424-3p might be related to Cr (VI)-induced cell apoptosis, and miR-221-3p might participate in Cr (VI)-induced DDR. We also found that the expression of miR-21-5p and miR-424-3p was upregulated in chromate workers. Conclusions: Cr (VI) exposure could significantly impact miRNAs expression in vitro and in chromate workers. Functional studies showed that miR-148a-3p, miR-21-5p and miR-221-3p might take a crucial role in the cellular DDR induced by Cr (VI) exposure. [ABSTRACT FROM AUTHOR]

• The 45S and 5S rDNA was amplificated in gastric tumor tissues. • The copy number of 45S rDNA was significantly elevated in P53 positive patients. • The rDNA variation in tumor tissues was associated with metal levels. The ribosomal DNA (rDNA) can act as a sensor and responder of cancer-associated stress. Here we investigated rDNA copy number in gastric cancers and its association with existing biomarkers and metals exposure. This study was performed on paired tumor and adjacent normal tissues obtained from 65 gastric cancer patients who underwent gastrectomy. Immunohistochemistry was used to assess HER-2, E-cadherin, EGFR, CK (pan), CK20, CK7, TopoⅡ, CAM5.2, P53, and Ki-67 expression. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the concentrations of 17 metals in gastric tissues. rDNA copy number was detected by qPCR in genomic DNA isolated from tissue samples. Associations between the expression of existing markers, metal concentrations, and rDNA copy number were evaluated. Within patients with gastric cancer, the copy number of the 45S rDNA components (18S, 5.8S, 28S) and the 5S rDNA in tumor tissues were significantly higher than those in adjacent normal tissues, whereas mitochondrial DNA (mtDNA) copy number was significantly lower in tumor tissues than that in adjacent normal tissues. Further analysis revealed that the increase in 18S, 5.8S, and 28S rDNA copy number in tumor tissues was diminished in the context of EGFR and P53 loss. Moreover, analysis of metals revealed particularly high concentrations of As, Cd, Cr, Cu and Fe in the gastric tissues of these patients. Intriguingly, rDNA copy number variation across individuals was correlated with the concentrations of some metals. The rDNA was amplified in tumor tissues of gastric cancer patients, and its amplification may be associated with metals exposure. The expression of EGFR and P53 may influence rDNA copy number, with diminished amplification of the rDNA in cancers that were negative for these biomarkers. Our observation further our understanding of rDNA copy number in gastric cancer and its potential as a simple and useful marker in gastric cancer monitoring. [ABSTRACT FROM AUTHOR]