Potential mechanisms of lung injury and repair after hexavalent chromium [Cr(VI)] aerosol whole-body dynamic exposure.

Hexavalent chromium [Cr(VI)], known as "Top Hazardous Substances", poses a significant threat to the respiratory system. Nevertheless, the potential mechanisms of toxicity and the lung's repair ability after injury remain incompletely understood. In this study, Cr(VI) aerosol whole-body dynamic exposure system simulating real exposure scenarios of chromate workers was constructed to evaluate the lung injury and repair effects. Subsequently, miRNA sequencing, mRNA sequencing and metabolomics analyses on lung tissue were performed to explore the underlying mechanisms. Our results revealed that Cr(VI) exposure led to an increase in lactic dehydrogenase activity and a time-dependent decline in lung function. Notably, after 13 w of Cr(VI) exposure, alveolar hemorrhage, thickening of alveolar walls, emphysema-like changes, mitochondrial damage of alveolar epithelial cells and macrophage polarization changes were observed. Remarkably, a two-week repair intervention effectively ameliorated lung function decline and pulmonary injury. Furthermore, significant disruptions in the expressions of miRNAs and mRNAs involved in oxidative phosphorylation, glycerophospholipid metabolism and inflammatory signaling pathways were found. The two-week repair period resulted in the reversal of expression of oxidative phosphorylation related genes, and inhibited the inflammatory signaling pathways. This study concluded that the inhibition of the mitochondrial oxidative phosphorylation pathway and the subsequent enhancement of inflammatory response might be key mechanisms underlying Cr(VI) pulmonary toxicity, and timely cessation of exposure could effectively alleviate the pulmonary injury. These findings shed light on the potential mechanisms of Cr(VI) toxicity and provide crucial insights into the health protection for occupational populations exposed to Cr(VI).

Two-week repair alleviates hexavalent chromium-induced hepatotoxicity, hepatic metabolic and gut microbial changes: A dynamic inhalation exposure model in male mice.

Hexavalent chromium [Cr(VI)] has been identified as a "Group I human carcinogen" with multisystem and multiorgan toxicity. A dynamic inhalation exposure model in male mice, coupled with the hepatic metabolome and gut microbiome, was used to explore hepatotoxicity, and hepatic metabolic and gut microbial changes under the exposure scenarios in the workspace and general environment. The present study set up an exposure group (EXP) that inhaled 150 µg Cr/m3 for 13 weeks, a control group (CONT) that inhaled purified air, as well as a two-week repair group (REXP) after 13 weeks of exposure and the corresponding control group (RCONT). Cr(VI) induced elevation of hepatic Cr accumulation, the ratio of ALT and AST, and folate in serum. Inflammatory infiltration in the liver and abnormal mitochondria in hepatocytes were also induced by Cr(VI). Glutathione, ascorbate, folic acid, pantetheine, 3'-dephospho-CoA and citraconic acid were the key metabolites affected by Cr(VI) that were associated with significant pathways such as pantothenate and CoA biosynthesis, hypoxia-inducible factor-1 signaling pathway, antifolate resistance, alpha-linolenic acid metabolism and one carbon pool by folate. g_Allobaculum was identified as a sensitive biomarker of Cr(VI) exposure because g_Allobaculum decreased under Cr(VI) exposure but increased after repair. The gut microbiota might be involved in the compensation of hepatotoxicity by increasing short-chain fatty acid-producing bacteria, including g_Lachnospiraceae_NK4A136_group, g_Blautia, and f_Muribaculaceae. After the two-week repair, the differential metabolites between the exposed and control groups were reduced from 73 to 29, and the KEGG enrichment pathways and differential microbiota also decreased. The mechanism for repair was associated with reversion of lipid peroxidation and energy metabolism, as well as activation of protective metabolic pathways, such as the AMPK signaling pathway, longevity regulating pathway, and oxidative phosphorylation. These findings might have theoretical and practical implications for better health risk assessment and management.

Blood chromium exposure, immune inflammation and genetic damage: Exploring associations and mediation effects in chromate exposed population.

Both genetic damage and inappropriate immune function are relevant to cancer of hexavalent chromium [Cr(VI)]. However, its associations with immune response and genetic damage development are poorly understood. To explore their associations and mediating effects, 1249 participants were included from the Occupational Chromate Exposure Dynamic Cohort, and their blood Cr concentrations were measured as internal exposure. A set of biomarkers including urinary 8-hydroxy-2' - deoxyguanosine (8-OHdG), micronucleus frequency (MNF) and mitochondrial DNA copy number (mtCN) was developed to evaluate the landscape of genetic damage of Cr(VI). Serum C-reactive protein (CRP) and first component of complement q (C1q) were measured to reflect immune inflammation. Multivariate linear regression and mediation analyses were applied to assess the potential associations and mediation effects. It was found that blood Cr level showed significant dose-dependent relationships with increasing of MNF and urinary 8-OHdG, while negative association with CRP and C1q. Furthermore, a 1-unit increase in CRP was associated with decreases of - 0.765 to - 0.254 in MNF, - 0.400 to - 0.051 in urinary 8-OHdG. 4.97% of the association between blood Cr level and the increased MNF was mediated by CRP. 11.58% of the relationship between concentration of blood Cr and urinary 8-OHdG was mediated by C1q. These findings suggested that Cr(VI) exposures might prompt genetic damage, possibly partial via worsening immune inflammation.

Analysis of serum metabolome of workers occupationally exposed to hexavalent chromium: A preliminary study.

Hexavalent chromium (Cr(VI)) compound is considered as a common environmental and occupational pollutant due to widespread application in industry and agriculture. Cr(VI) as a carcinogen poses a serious threat to human health and the underlying mechanisms need further investigation. Previous studies had demonstrated the characteristic expression profiling after Cr(VI) treatment in vitro and in vivo at the levels of gene and protein. The comprehensive metabolic signatures were also conducive to discover potential biomarkers for effects assessment of Cr(VI) toxicity. In the current study, Ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) non-targeted metabolomics was applied to analyze serum metabolic changes in 77 chromate exposure workers and 62 controls. Thirteen metabolites were found significantly decreased and 41 metabolites were increased, which were involved in arginine and proline metabolism, and glycerophospholipid metabolism by bioinformatic analysis. Furthermore, there were significant negative correlations between blood Cr level and Arginine, PC(18:2/24:4) and PC(14:0/16:0), subgroup analyses indicated that these correlations were observed in male-only subgroups, and were not found among chromate workers and controls separately. Diet could be a potential confounder which was not controlled rigorously in this study. These findings provided preliminary clues to investigate the underlying mechanisms of Cr(VI)-induced toxicity and were required to be further verified in future researches.

The Effect of Global DNA Methylation on PDCD5 Expression in the PBMC of Occupational Chromate Exposed Workers.

OBJECTIVES: To evaluate the alteration of protein of programmed cell death 5 (PDCD5) in peripheral blood mononuclear cells (PBMC) and DNA methylation caused by hexavalent chromium exposure. METHODS: There were 112 workers and 56 controls in this study. The chromium in RBC and urine, PBMC with PDCD5+, DNA methylation, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and score of DNA damage were measured. RESULTS: In chromate exposed workers, the percent of PBMC with PDCD5+, urine 8-OHdG, and score of DNA damage were significantly higher, whereas global DNA methylation was significantly lower. The binary logistic regression and generalized linear mixed model analysis showed that the percent of PBMC with PDCD5+ was significantly associated with global DNA hypomethylation. CONCLUSIONS: The aberrant DNA hypomethylation plays an important role in PBMC apoptosis of occupational hexavalent chromium exposure.

A Novel Transcriptome Integrated Network Approach Identifies the Key Driver lncRNA Involved in Cell Cycle With Chromium (VI)-Treated BEAS-2B Cells.

Hexavalent chromium [Cr(VI)] is a well-known occupational carcinogen, but the mechanisms contributing to DNA damage and cell cycle alternation have not been fully characterized. To study the dose-response effects of Cr(VI) on transcription, we exposed BEAS-2B cells to Cr(VI) at concentrations of 0.2, 0.6, and 1.8 µmol/L for 24 h. Here, we identified 1,484 differentially expressed genes (DEGs) in our transcript profiling data, with the majority of differentially expressed transcripts being downregulated. Our results also showed that these DEGs were enriched in pathways associated with the cell cycle, including DNA replication, chromatin assembly, and DNA repair. Using the differential expressed genes related to cell cycle, a weighted gene co-expression network was constructed and a key mRNA-lncRNA regulation module was identified under a scale-free network with topological properties. Additionally, key driver analysis (KDA) was applied to the mRNA-lncRNA regulation module to identify the driver genes. The KDA revealed that ARD3 (FDR = 1.46 × 10-22), SND1 (FDR = 5.24 × 10-8), and lnc-DHX32-2:1 (FDR = 1.43 × 10-17) were particularly highlighted in the category of G2/M, G1/S, and M phases. Moreover, several genes we identified exhibited great connectivity in our causal gene network with every key driver gene, including CDK14, POLA1, lnc-NCS1-2:1, and lnc-FOXK1-4:1 (all FDR < 0.05 in those phases). Together, these results obtained using mathematical approaches and bioinformatics algorithmics might provide potential new mechanisms involved in the cytotoxicity induced by Cr.

Modulation of homologous recombination repair gene polymorphisms on genetic damage in chromate exposed workers.

Hexavalent chromium [Cr(VI)] is one of the most common environmental carcinogens, which is associated with DNA damage, genetic instability and increase the risk of cancer development. However, the mechanisms of genetic damage induced by Cr(VI) remains to be thoroughly illustrated. A molecular epidemiological study was conducted on 120 chromate exposed workers and 97 controls. Results indicated that,the rs12432907 of XRCC3 carrying T allele, the rs144848 of BRCA2 with C allele and the rs1805800 of NBS1 with genotype(TT) of individuals were associated with lower genetic damage, while the rs2295152 of XRCC3 carrying T allele, the rs13312986 (CC and CT genotypes) and the rs2697679 of NBS1 with A allele were associated with higher genetic damage in workers exposed to chromate. The interaction of chromate exposure with rs2295152 of XRCC3 had a significant effect on micronuclei frequency (MNF). The gene polymorphisms in homologous recombination repair pathway could modulate chromate-induced genetic damage.

LncRNA expression profiling and its relationship with DNA damage in Cr(VI)-treated 16HBE cells.

Compounds containing hexavalent chromium [Cr(VI)] were Group I human carcinogens which were mutagenic and can induce DNA damage. Cr(VI) exposure could cause a lot of changes in mRNA, protein and microRNA expression as well as DNA methylation. There were still few studies on the role of long non-coding RNA (lncRNA) in the carcinogenic process of Cr(VI). In current study, lncRNA expression profiling and bioinformatics analysis in 16HBE cells treated by Cr(VI) were performed. The cell counting kit-8 (CCK-8) assay and the comet assay were done to assess the cell viability and DNA damage in Cr(VI)-treated 16HBE cells respectively. The lncRNA expression profile was performed by Arraystar Microarray V3.0 in 16HBE cells treated with 0.00 and 10.00 µmol/L Cr(VI). Real-time quantitative polymerase chain reaction (RT-qPCR) was applied to verify some significantly altered lncRNAs. Gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) analysis and mRNA-lncRNA network analysis were conducted to identify related biological processes, signal pathway and critical lncRNAs. It was found that Cr(VI) could induce cells viability decline and alter lncRNA expression profile of 16HBE cells. 1868 lncRNAs were significantly up-regulated and 2203 lncRNAs were significantly down-regulated which formed a complex regulation network. With the increase of Cr(VI) concentration, some lncRNAs increased or decreased gradually. The differentially expressed LncRNA profiling induced by Cr(VI) were associated with immune response, cell cycle, DNA damage and repair and so on. RP11-388M20.9 and AC092620.3 were nonlinearly decreasing with the change of the DNA content of comet tails (Tail DNA), tail length (TLL), tail moment (TM) and Olive Tail Moment (OTM), and the fitting results of Tail DNA and TM were statistically significant (P < 0.05). It was possible for RP11-388M20.9 to regulate DNA damage by interacting with the target gene after Cr(VI) exposure, and was likely to be a potential biomarker of DNA damage in Cr(VI)-treated 16HBE cells.