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.

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.

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.

Metabolomics screening of serum biomarkers for occupational exposure of titanium dioxide nanoparticles.

Although nanotoxicology studies have shown that respiratory exposure of titanium dioxide nanoparticles (TiO2 NPs) could induce adverse health effects, limited biomarkers associated with occupational exposure of TiO2 NPs were reported. The purpose of this study is to screen serum biomarkers among workers occupationally exposed to TiO2 NPs using metabolomics. Compared with the control group, a total of 296 serum metabolites were differentially expressed in the TiO2 NPs-exposed group, of which the relative expression of 265 metabolites increased, and the remaining 31 decreased. Three machine learning methods including random forest (RF), support vector machines (SVM), and boruta screened eight potential biomarkers and simultaneously selected a metabolite, Liquoric acid. Through multiple linear regression analysis to adjust the influence of confounding factors such as gender, age, BMI, smoking and drinking, occupational exposure to TiO2 NPs was significantly related to the relative expression of the eight potential biomarkers. Meanwhile, the receiver operating characteristic curves (ROCs) of these potential biomarkers had good sensitivity and specificity. These potential biomarkers were related to lipid peroxidation, and had biological basis for occupational exposure to TiO2 NPs. Therefore, it was demonstrated that the serum metabolites represented by Liquoric acid were good biomarkers of occupational exposure to TiO2 NPs.

Perspectives of Genetic Damage and Epigenetic Alterations by Hexavalent Chromium: Time Evolution Based on a Bibliometric Analysis.

Compounds containing hexavalent chromium [Cr(VI)] have been classified as Group I human carcinogens in 1990 by the International Agency for Research on Cancer, known to induce human lung cancers. To determine the nature of Cr(VI) carcinogenesis, much has been learned about genetic damage and epigenetic alterations. On the basis of bibliometric analysis of the available literature found between 1966 and 2020, the present study investigated the evolution of author keywords; provided a summary of relevant studies focused on populations, animals/plants, or cells; and depicted the co-operation among countries or institutions and research group development. Additionally, multiomics technology and bioinformatics analysis can be a valuable tool for figuring out new biomarkers from different molecular levels like gene, RNA, protein, and metabolite and ascertaining the mechanism pathways of Cr(VI) genotoxicity and carcinogenesis.

Association between coronavirus disease 2019 (COVID-19) and long-term exposure to air pollution: Evidence from the first epidemic wave in China.

People with chronic obstructive pulmonary disease, cardiovascular disease, or hypertension have a high risk of developing severe coronavirus disease 2019 (COVID-19) and of COVID-19 mortality. However, the association between long-term exposure to air pollutants, which increases cardiopulmonary damage, and vulnerability to COVID-19 has not yet been fully established. We collected data of confirmed COVID-19 cases during the first wave of the epidemic in mainland China. We fitted a generalized linear model using city-level COVID-19 cases and severe cases as the outcome, and long-term average air pollutant levels as the exposure. Our analysis was adjusted using several variables, including a mobile phone dataset, covering human movement from Wuhan before the travel ban and movements within each city during the period of the emergency response. Other variables included smoking prevalence, climate data, socioeconomic data, education level, and number of hospital beds for 324 cities in China. After adjusting for human mobility and socioeconomic factors, we found an increase of 37.8% (95% confidence interval [CI]: 23.8%-52.0%), 32.3% (95% CI: 22.5%-42.4%), and 14.2% (7.9%-20.5%) in the number of COVID-19 cases for every 10-µg/m3 increase in long-term exposure to NO2, PM2.5, and PM10, respectively. However, when stratifying the data according to population size, the association became non-significant. The present results are derived from a large, newly compiled and geocoded repository of population and epidemiological data relevant to COVID-19. The findings suggested that air pollution may be related to population vulnerability to COVID-19 infection, although the extent to which this relationship is confounded by city population density needs further exploration.

Exploring urine biomarkers of early health effects for occupational exposure to titanium dioxide nanoparticles using metabolomics.

Many experimental studies have demonstrated that titanium dioxide nanoparticles (TiO2 NPs) could induce adverse health effects in vivo and in vitro. But epidemiological evidence and biomarkers related to early health effects are still lacking. This study aimed to explore biomarkers in the urine samples of workers occupationally exposed to a relatively low concentration of TiO2 NPs. A cross-sectional study was conducted in Jinan, China, involving 132 employees of a TiO2 NP manufacturing plant, among which the exposed group and control group were 1 : 1 matched by confounding factors such as gender, age, BMI, smoking and drinking. Untargeted metabolomics was performed in urine samples using high performance liquid chromatography-mass spectrometry (HPLC-MS) technology. The differential metabolites between the TiO2 NP exposed group and the control group were analyzed and then screened for potential biomarkers using bioinformatics methods. Metabolomics found a total of 1760 differentially expressed metabolites in the TiO2 NP exposed group, of which 60 differential metabolites were simultaneously confirmed by one-dimensional and multi-dimensional statistical analysis. Among these 60 differential metabolites, the relative expression of 27 metabolites increased, and the remaining 33 decreased. Pathway enrichment analysis further found that the metabolic pathway of long chain acyl-coa dehydrogenase deficiency (Lcad) was significantly enriched. Ten differential metabolites were selected as potential biomarkers of occupational exposure to TiO2 NPs using machine learning methods, including dibenzyl ether, quassimarin, tryptophan, etc. The receiver operating characteristic curves (ROCs) of these potential biomarkers showed good sensitivity and specificity. These potential biomarkers also had biological basis for occupational exposure to TiO2 NPs. Therefore, urine metabolites represented by dibenzyl ether are considered as good biomarkers of early health effects for occupational exposure to TiO2 NPs.

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.

Gene expression profiling and bioinformatics analysis in 16HBE cells treated by chromium (VI).

Hexavalent chromium [Cr(VI)] compounds are widely used in industry and agriculture and are also ubiquitous environmental contaminant which are recognized as one kind of carcinogen, mutagen and teratogen towards humans and animals. To determined the Cr(VI) toxicity effects, gene expression profile can be meaningful for discovering underlying mechanisms of toxicity, and identifying potential specific genetic markers of Cr(VI) exposure and effects. In the current study, gene expression profiling and bioinformatics analysis in 16HBE cells treated by chromium(VI) compound were performed. The MTT assay was done to determine the optimal Cr(VI) treated concentration and time. The mRNA expression profile was performed using Arraystar Microarray V3.0 at 10.00µM Cr(VI). RT-qPCR was applied to verify some interested significantly altered genes at different treatment groups. Comprehensive analysis including biological processes, GO ontology network, pathway network analysis and gene-gene network analysis was conducted to identify the related biological processes, signal pathway and critical genes. It was found that Cr(VI) could induce reduced cells viability and alter gene expression profile of human bronchial epithelial cells. 2273 significantly differential expressed genes formed a complex network and some expressions changed in a Cr(VI) concentration dependent manner. In conclusion, Cr(VI) toxicity effects may involve in oxidative stress, inflammation, energy metabolism, protein synthesis endocytosis, ion binding, DNA binding and metabolism, cell morphogenesis, cell cycle regulation, autophagy, apoptosis, cell death, and carcinogenesis by some specific pathway. Meanwhile, some significantly differential expression genes can be used as potential biomarkers of Cr(VI) exposure.