Immune Regulation Patterns in Response to Environmental Pollutant Chromate Exposure-Related Genetic Damage: A Cross-Sectional Study Applying Machine Learning Methods.

Exposure to hexavalent chromium damages genetic materials like DNA and chromosomes, further elevating cancer risk, yet research rarely focuses on related immunological mechanisms, which play an important role in the occurrence and development of cancer. We investigated the association between blood chromium (Cr) levels and genetic damage biomarkers as well as the immune regulatory mechanism involved, such as costimulatory molecules, in 120 workers exposed to chromates. Higher blood Cr levels were linearly correlated with higher genetic damage, reflected by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and blood micronucleus frequency (MNF). Exploratory factor analysis revealed that both positive and negative immune regulation patterns were positively associated with blood Cr. Specifically, higher levels of programmed cell death protein 1 (PD-1; mediated proportion: 4.12%), programmed cell death ligand 1 (PD-L1; 5.22%), lymphocyte activation gene 3 (LAG-3; 2.11%), and their constitutive positive immune regulation pattern (5.86%) indirectly positively influenced the relationship between blood Cr and urinary 8-OHdG. NOD-like receptor family pyrin domain containing 3 (NLRP3) positively affected the association between blood Cr levels and inflammatory immunity. This study, using machine learning, investigated immune regulation and its potential role in chromate-induced genetic damage, providing insights into complex relationships and emphasizing the need for further research.

Relationships between blood chromium exposure and liver injury: Exploring the mediating role of systemic inflammation in a chromate-exposed population.

Hexavalent chromium and its compounds are prevalent pollutants, especially in the work environment, pose a significant risk for multisystem toxicity and cancers. While it is known that chromium accumulation in the liver can cause damage, the dose-response relationship between blood chromium (Cr) and liver injury, as well as the possible potential toxic mechanisms involved, remains poorly understood. To address this, we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL), and to evaluate the mediating effects of systemic inflammation. Platelet (PLT) and the platelet-to-lymphocyte ratio (PLR) were utilized as biomarkers of systemic inflammation. In the linear mixed-effects analyses, each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82% (0.11%, 1.53%) in TBIL, 1.67% (0.06%, 3.28%) in DBIL, 0.73% (0.04%, 1.43%) in ALT and 2.08% (0.29%, 3.87%) in AST, respectively. Furthermore, PLT mediated 10.04%, 11.35%, and 10.77% increases in TBIL, DBIL, and ALT levels induced by chromate, respectively. In addition, PLR mediated 8.26% and 15.58% of the association between blood Cr and TBIL or ALT. These findings shed light on the mechanisms underlying blood Cr-induced liver injury, which is partly due to worsening systemic inflammation.

MiR-1696/GPx3 axis is involved in oxidative stress mediated neutrophil extracellular traps inhibition in chicken neutrophils.

As an important immune mechanism of neutrophils, the release of Web-like chromatin structures known as neutrophil extracellular traps (NETs) can rapidly locate and capture invading pathogens, which has received sustained attention. There are still some fundamental questions surrounding established studies on the mechanism of balance between reactive oxygen species (ROS) dependent release and neutrophil antioxidant response. Glutathione peroxidase 3 (GPx3) is an important antioxidant protein and has been identified can regulate the immune response. However, the effect of GPx3 on the NETs formation and microRNA in this process remain poorly understood. In the present study, we used chicken peripheral blood neutrophils treated with Phorbol-12-myristate-13-acetate (PMA) for 3 h as NETs formation model. The result of morphological observation showed that GPx3 inactivation compromised the release of NETs. Further analysis revealed that knockdown of GPx3 significantly disturbed oxidative balance by inhibiting antioxidant enzymes activity and increasing H2 O2 content. Quantitative analysis of NETs-related genes found that the phosphorylation level of mitogen-activated protein kinase (MAPK) pathway genes (ERK, JNK, and p38) and expression of phosphoinositide-3-kinase (PI3K)/AKT pathway genes (PI3K and AKT) were suppressed with the downregulation of GPx3. Meanwhile, we identified that miR-1696 can target GPx3 expression by using dual luciferase reporter system. Additionally, overexpression of miR-1696 can not only inhibit the formation of NETs by restraining the expression of GPx3, interfering with the generation of ROS and activation of the MAPK and PI3K/AKT pathways, but also reducing the release of PMA-induced NETs promoted by overexpression of GPx3. These results provide evidence that miR-1696 targeted GPx3 activities in neutrophils could be used to regulate the NETs formation stimulated by PMA.

DEHP-induce damage in grass carp hepatocytes and the remedy of Eucalyptol.

The wide application of plastic products led to the wide exposure of plasticizer in environment. As a new environmental pollutant, plasticizers' toxicity researches were far from enough in fish. In order to further explore these mechanisms, we used Diethylhexyl phthalate (DEHP), a common plasticizer, treated the grass carp hepatocytes, and selected Eucalyptol (EUC) to study its antagonistic effect on DEHP. The results showed that after DEHP exposure, oxidative stress level and inflammation in grass carp hepatocytes were increased, and then mRNA and protein expression of apoptosis related markers were increased significantly, leading to hepatocytes apoptosis. Moreover, AO/EB staining and Hoethst staining also showed that the number of apoptotic cells increased after DEHP exposure. It should be noted that both EUC pretreatment and EUC simultaneous treatment could alleviate the oxidative stress, levels of inflammatory factors and apoptosis induced by DEHP. In comparison, the effect of EUC simultaneous treatment was better. Our results showed that DEHP induced apoptosis in grass carp hepatocytes through oxidative stress and inflammation, while EUC could alleviate apoptosis by reducing oxidative stress and inflammation caused by DEHP. The innovation of this study was to explore the interaction between DEHP and EUC for the first time. This study found that DEHP could cause apoptosis in grass carp hepatocytes through oxidative stress and inflammation; EUC had a good antagonistic effect on a series of damage in grass carp hepatocytes caused by DEHP, and EUC pretreatment and simultaneous treatment had a certain effect, among which, simultaneous treatment had a better effect. This study enriched the theoretical mechanism of DEHP toxicity in fish hepatocytes, and put forward the methods to solve the toxicity of DEHP.

Atrazine exposure triggers common carp neutrophil apoptosis via the CYP450s/ROS pathway.

Due to the excessive pursuit of crop yields and the abuse of herbicides, water pollution caused by atrazine (ATR) has become one of the most severe environmental issues threatening the health of fish and aquatic animals. However, no detailed report has been conducted on the mechanisms of ATR immunotoxicity in fish neutrophils. To investigate these mechanism, we exposed peripheral blood neutrophils to 25 µg/ml atrazine for 1, 2, and 3 h. The results showed that ATR induced the mRNA expression of CYPs enzymes (CYP1A1, CYP1B1, CYP1C and CYP3A138), which increased the ROS levels, and inhibited the SOD and CAT activities, GSH content and spurred the accumulation of MDA. Additionally, a significant decline in the OXPHOS, Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities of mitochondria was observed after ATR exposure. Concurrently, ATR activated Caspase3 and induced apoptosis by changing the expression of mitochondrial pathway factors (Bcl-2, BAX, Caspase9) and death receptor pathway major genes (TNF-α, TNFR, Fas, FasL, and Caspase8). The results reported here indicate that the oxidative stress and mitochondrial damage caused by ATR metabolism may play a crucial role in the apoptosis of carp neutrophils, and enrich the immunotoxicological mechanisms of ATR observed in fish.

Chlorpyrifos induced oxidative stress to promote apoptosis and autophagy through the regulation of miR-19a-AMPK axis in common carp.

Chlorpyrifos (CPF) has become a mainly pollution in water environment. Micro-RNAs (miRNAs) play an important part in the development of apoptosis and autophagy. However, the potential mechanism of CPF induced kidney toxicity and the roles of miRNAs are still unclear. To explore the underlying mechanism, the kidney of common carp exposed to different concentrations of CPF for 40 days was used as a research object. We found that CPF could damage the ultrastructure and function of kidney; and also caused antioxidant system disorder. CPF inhibited the mRNA level of miR-19a which improved AMP-activated protein kinase (AMPK). Furthermore, the detection of apoptosis and autophagy relative genes showed that the expressions of TSC complex subunit 2 (TSC2), light chain 3 (LC3), Dynein, tumor protein 53 (p53), Bcl-2 associated X protein (Bax), caspase-3 and caspase-9 were enhanced and the expressions of nechanistic target of rapamycin (mTOR), Ras homolog mTORC1 binding (Rheb) and B-cell lymphoma (Bcl-2) were reduced in dose-dependent way. Taken together, we conclude that CPF causes oxidative stress and miR-19a-AMPK axis disorder, thereby promotes apoptosis and autophagy in common carp kidney. Our study will provide theoretical basis for toxicology research and environmental protection of CPF.

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).

Cellular senescence mediates hexavalent chromium-associated lung function decline: Insights from a structural equation Model.

There is sufficient evidence suggesting that exposure to hexavalent chromium [Cr(VI)] can cause a decline in lung function and the onset of lung diseases. However, no studies have yet explored the underlying mechanisms of these effects from various perspectives such as systemic inflammation, oxidative stress, and cellular senescence, simultaneously. This cross-sectional study was conducted among 304 workers engaged in chromate production and processing in China. Urine was used for detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin F2α (8-iso-PGF2α), while RNA and DNA extraction from peripheral blood cells was used for detection of mRNA, telomere length, and ribosomal DNA copy numbers (rDNA CNs). A 2.7-fold elevation in blood chromate (Cr) corresponded to a 7.86% (95% CI: 2.57%, 13.42%) rise in urinary 8-OHdG and a 4.14% (0.02%, 8.42%) increase in urinary 8-iso-PGF2α, indicating that exposure to chromates can cause oxidative stress. Furthermore, strong correlations emerged between blood Cr concentration and mRNA levels of P16, P21, TP53, and P15 in the cellular senescence pathway. Simultaneously, a 2.7-fold elevation in blood Cr associated with a -5.47% (-8.72%, -2.1%) change in telomere length, while rDNA CNs (5S, 5.8S, 18S, and 28S) changed by -3.91% (-7.99%, 0.34%), -9.4% (-15.73%, -2.6%), -8.06% (-14.01%, -1.69%), and -5.86% (-10.67%, -0.78%), respectively. Structural equation model highlighted that cellular senescence exerted significant indirect effects on Cr(VI)-associated lung function decline, with a mediation proportion of 23.3%. This study provided data supporting for 8-iso-PGF2α, telomere length, and rDNA CNs as novel biomarkers of chromate exposure, emphasizing the significant role of cellular senescence in the mechanism underlying chromate-induced lung function decline.

Relationship between systemic inflammation and lung injury induced by chromate exposure: A cross-sectional study in workers.

Hexavalent chromium [Cr(VI)] compounds, known as "Group I Human Carcinogen" and "Category I Respiratory Sensitizer", posed great challenges to the respiratory system. A cross-sectional study was undertaken among chromate workers. Serum club cell protein 16 (CC16) and soluble urokinase-type plasminogen activator receptor (suPAR) were measured using ELISA. Thirteen macrophage-related mediators were tested using cytometric bead array. After controlling for sex, age, smoking status, drinking status and BMI, each increase of one-unit of Ln-transformed blood Cr was related to the increase of IL-1beta [Beta (95% CI), 7.22(1.14, 13.29)%, P = 0.021], IL-23 [8.5(1.15, 15.85)%, P = 0.021], IFN-gamma [3.14(0.15, 6.13)%, P = 0.040], and suPAR [9.31(2.5, 16.12) %, P = 0.008], as well as the increase of CC16 by 3.88(0.42, 7.34) % (P = 0.029). Moreover, these inflammatory mediators played an mediation role in the rise of CC16 caused by Cr(VI). The exposure-response curve analysis revealed a substantial nonlinear association of IFN-gamma and suPAR with CC16, thus the mediation effect of INF-gamma and suPAR required cautious interpretation. The positive connection between macrophage-related mediators was stronger in the high exposure group than in the low exposure group, suggesting that high concentration of chromate might promote a complex interplay within the immune system.

Hexavalent chromium induces γH2AX and RAD51 involved in DNA damage repair in BEAS-2B cells by modulating LNC-DHFR-4:1.

Hexavalent chromium [Cr(VI)] is rarely found in nature. Its occurrence in the environment is mainly due to anthropogenic sources. Our previous studies have shown that Cr(VI) exposure could change the expression profile of long noncoding RNAs (lncRNAs). However, the relationship between lncRNAs and genetic damage induced by Cr(VI) remains unclear. In this study, RT-qPCR was used to verify the expression of genes and lncRNAs involved in DNA damage repair in BEAS-2B cells exposed to different Cr(VI) concentrations. After screening out LNC-DHFR-4:1, overexpression and knockdown models of BEAS-2B cells were used to further identify the relationship between the lncRNA and RAD51. RT-qPCR and indirect immunofluorescence were used to detect expression. Our results revealed that with increasing Cr(VI) concentration, γH2AX expression was increased, while the expression of RAD51 was decreased. Meanwhile, LNC-DHFR-4:1 acted as a competitive endogenous RNA to regulate the expression of γH2AX and RAD51, which further affected DNA damage repair. The overexpression of LNC-DHFR-4:1 induced a twofold decrease in γH2AX and a onefold increase in RAD51, and its knockdown showed the opposite results. These results suggested that LNC-DHFR-4:1 might be a potential biomarker of Cr(VI)-induced DNA damage repair in BEAS-2B cells.

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.

Effects of short-term high-concentration exposure to PM2.5 on pulmonary tissue damage and repair ability as well as innate immune events.

Short-term heavy air pollution still occurs frequently worldwide, especially during the winter heating period in some developing countries, which is usually accompanied by the temporary explosive growth of PM2.5. The pulmonary damage caused by PM2.5 exposure has been determined, but there have been few studies on the repair ability after the cessation of exposure and the important role of innate immune events. This study established a short-term (30 days) high-concentration (15 mg/kg body weight) PM2.5 exposure and recovery (15 days of exposure cessation) model by intratracheal instillation. The results showed that short-term PM2.5 exposure increased the content of collagen fiber in rat lung tissue, which was significantly repaired after recovery by 15 days of exposure cessation. Meanwhile, exposure to PM2.5 also caused changes in lung epithelial function, macrophage polarization and cell autophagy function. Most of these changes could be restored or reversed to a certain extent after recovery. However, there were also some biomarkers, including CLDN18.1, SP-A, SP-D, iNOS, CD206, Beclin1, p62 and LC3B, that were still significantly different between the exposure and control groups after recovery, suggesting that some toxic effects, especially epithelial function damage, were not completely repaired. In addition, there was a significant correlation between pulmonary fibrosis and innate immunity. The present study demonstrated that short-term high-concentration exposure to PM2.5 could cause temporary lung tissue damage and related innate immune events in rats, and the repair ability existed after the cessation of exposure, but part of the damage that required special attention still persisted.

Triglyceride-Glucose Index Correlate With Telomere Length in Healthy Adults From the National Health and Nutrition Examination Survey.

Aim: The present investigation was designed to test the association between leukocyte telomere length (LTL) and two simple markers of insulin resistance, that is, homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride-glucose (TyG) index in U.S. adults without metabolic diseases. Methods: A total of 6489 U.S. adults without diabetes from NHANES 1999-2002 were analyzed. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. HOMA-Index was calculated as fasting plasma glucose (mmol/L) × fasting serum insulin (mU/mL)/22.5. LTL was obtained using the quantitative polymerase chain reaction method. Multivariate linear regression analysis was assessed to evaluate the association of TyG index HOMA-IR with LTL. We further conducted a generalized additive model (GAM) and a fitted smoothing curve with penalized spline method. Results: It was found that the mean LTL was 5796.1 bp in the measured healthy adults. Overall, TyG index was significantly associated with LTL, while HOMA-IR was not. Compared with participants in tertile 1 of the TyG index, the ß (95% CI) for those in the second (8.27 to 8.77) and third (≥ 8.77) were -4.31 (95% CI: -48.12~39.49) and -95.98 (95% CI: -145.08~-46.89), respectively. Subjects with TyG index ≥ 8.77 had statistically significant shorter LTL (ß = -93.33, 95%CI: -134.33~-52.32), compared with TyG index < 8.77. We further explored a dose-response relation between TyG index by a decile approach [≤ 7.81 (reference), 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, 8.52-8.68, 8.68-8.83, 8.83-9.03, 9.03-9.33, and >9.33] and LTL. Five subgroups (TyG index 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, and 8.52-8.68) did not show significant effect on LTL; while there was a significantly shorter LTL for participants with the TyG index > 8.68, supporting a threshold effect of TyG index on LTL. Conclusions: The results suggested that higher TyG index (> 8.68) was closely related to shorter LTL and the TyG index was better associated with LTL than HOMA-IR.

Genetic damage and potential mechanism exploration under different air pollution patterns by multi-omics.

Ambient air pollution was classified as carcinogenic to humans (Group 1) for lung cancer. DNA damage was an important first step in the process of carcinogenesis, and could also be induced by air pollution. In this study, intratracheal instillation and real-time air exposure system were combined to establish SHP (short-term high-level PM2.5) and LLPO (long-term low-level PM2.5 and O3) exposure patterns, respectively. Hierarchical levels of genetic biomarkers were analyzed to explore DNA damage effects in rats. Representative DNA repair genes from different repair pathways were selected to explore the relative expression levels. The methylation level of differentially expressed repair genes were also determined. Besides, miRNA sequencing and non-targeted metabolomic analysis were performed in rat lungs. KEGG and multi-omics analysis were used to explore the potential mechanism of genetic damage under different air pollution patterns. We found that LLPO exposure induced DSBs and chromosome damage. SHP exposure could induce DSBs and DNA oxidative damage, and the effects of genetic damage under this pollution pattern could be repaired by natural repair. Repair genes involved in two pattern were different. SHP exposure could induce higher methylation levels of RAD51, which might be a potential epigenetic mechanism for high-level PM2.5 induced down-regulated expression of RAD51 and DSBs. Besides, 29 overlapped alterations in metabolic pathways were identified by metabolomic and miRNA sequencing, including purine metabolism and pyrimidine metabolism after LLPO exposure. Differential miRNAs expression in lung tissue were associated with apoptosis, DNA damage and damage repair. We concluded that under different air pollution patterns, DNA damage biomarkers and activated targets of DNA damage repair network were both different. The genetic damage effects caused by high-level short-term PM2.5 can be alleviated by natural repair. We provided possible mechanisms by multi-omics which could explain the increased carcinogenic risk caused by air pollution.

DNA damage, serum metabolomic alteration and carcinogenic risk associated with low-level air pollution.

Outdoor air pollution has been classified as carcinogenic to humans (Group 1) for lung cancer, but the underlying mechanism and key toxic components remain incompletely understood. Since DNA damage and metabolite alterations are associated with cancer progression, exploring potential mechanisms linking air pollution and cancer might be meaningful. In this study, a real-time ambient air exposure system was established to simulate the real-world environment of adult male SD rats in Beijing from June 13th, 2018, to October 8th, 2018. 8-OHdG in the urine, γ-H2AX in the lungs and mtDNA copy number in the peripheral blood were analyzed to explore DNA damage at different levels. Serum non-targeted metabolomics analysis was performed. Pair-wise spearman was used to explore the correlation between DNA damage biomarkers and serum differential metabolites. Carcinogenic risks of heavy metals and PAHs via inhalation were assessed according to US EPA guidelines. Results showed that PM2.5 and O3 were the major air pollutants in the exposure group and not detected in the control group. Compared with control group, higher levels of 8-OHdG, mtDNA copy number, γ-H2AX and PCNA-positive nuclei cells were observed in the exposure group. Histopathological evaluation suggested ambient air induced alveolar wall thickening and inflammatory cell infiltration in lungs. Perturbed metabolic pathways identified included glycolysis/gluconeogenesis metabolism, purine and pyrimidine metabolism, etc. γ-H2AX was positively correlated with serum ADP, 3-phospho-D-glyceroyl phosphate and N-acetyl-D-glucosamine. The BaPeq was 0.120 ng/m3. Risks of Cr(VI), As, V, BaP, BaA and BbF were above 1 × 10-6. We concluded that low-level air pollution was associated with DNA damage and serum metabolomic alterations in rats. Cr(VI) and BaP were identified as key carcinogenic components in PM2.5. Our results provided experimental evidence for hazard identification and risk assessment of low-level air pollution.

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.

Lung function assessment and its association with blood chromium in a chromate exposed population.

Hexavalent chromium [Cr(VI)] and its compounds have been associated with various respiratory diseases, while few studies have attempted to determine its adverse effect on lung function. To explore the potential early indicators of health surveillance for respiratory diseases induced by chromate exposure, a longitudinal cohort study including 515 workers with 918 measurements across 2010-2017 was conducted to investigate the impact of individual internal exposure on lung function. Inductively coupled plasma mass spectrometry (ICP-MS) and spirometry were used to measure whole blood chromium (blood Cr) and lung function respectively. In the linear mixed-effects analysis, each 1- unit increase in Ln- transformed blood Cr was significantly associated with estimated effect percentage decreases of 1.80 (0.35, 3.15) % in FEV1, 0.77 (0.10, 1.43) % in FEV1/FVC, 2.78 (0.55, 4.98) % in PEF, and 2.73 (0.59, 4.71) % in FEF25-75% after adjusting for related covariates. Exposure- response curve depicted the reduction of lung function with blood Cr increase, and the reference value of blood Cr was proposed as 6 µg/L considering the lung function as health outcome. Based on the repeated-measure analysis, compared with the low frequency group, subjects with high frequency of high exposure across 2010-2017 had an additional reduction of 5.65 (0, 11.3) % in FVC. Subjects with medium frequency showed more obvious declines of 9.48 (4.16, 14.87) % in FVC, 8.63 (3.49, 13.97) % in FEV1, 12.94 (3.34, 22.53) % in PEF and 10.97 (3.63, 18.30) % in MVV. These findings suggested that short- term high exposure to Cr associated with obstructive ventilatory impairment, and long- term exposure further led to restrictive ventilatory impairment.

Selenomethionine alleviates LPS-induced JNK/NLRP3 inflammasome-dependent necroptosis by modulating miR-15a and oxidative stress in chicken lungs.

Selenium (Se) was involved in many physiological processes in humans and animals. microRNAs (miRNAs) also played important roles in lung diseases. However, the regulatory mechanism of miRNA in chicken lungs and the mechanism of lipopolysaccharide (LPS)-induced pneumonia remained unclear. To further study these mechanisms, we established a supplement of selenomethionine (SeMet) and/or LPS-treated chicken model and a cell model of LPS and/or high and low expression of miR-15a in chicken hepatocellular carcinoma (LMH) cells. We detected the expression of some selenoproteins, p-c-Jun N-terminal kinase (JNK), nod-like receptor protein 3 (NLRP3), caspase1, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), mixed lineage kinase domain-like pseudokinase (MLKL), miR-15a, and oxidative stress kits. Additionally, we observed the morphology of lungs by H.E. staining in vitro. The results indicated that necroptosis occurred in LPS-treated chicken and LMH cells. Moreover, LPS stimulation inhibited miR-15a, and increased the expression of JNK, NLRP3, caspase1, RIPK1, RIPK3, and MLKL. We also found that LPS treatment not only increased the content of H2O2 and MDA in the lungs but also increased the activities of iNOS and CAT and the content of GSH decreased. Conclusion: SeMet could reduce the oxidative damage and activate NLRP3 inflammasome reaction by stimulating miR-15a/JNK, thus reduced the pulmonary necroptosis induced by LPS.

Inhibition of Lipopolysaccharide-Induced Inflammation of Chicken Liver Tissue by Selenomethionine via TLR4-NF-κB-NLRP3 Signaling Pathway.

Selenium (Se) is important in many physiological processes, such as antioxidant processes and inflammation. The aim of our experiments was to investigate the molecular mechanism that selenomethionine could reduce the lipopolysaccharide (LPS)-induced inflammation by inhibiting the TLR4-NF-κB-NLRP3 signaling pathway. Eighty broilers were randomly and evenly divided into two groups, giving normal Se content diets (Con group, 0.2 mg Se/kg diet) and Se-rich basal diets (Se group, 0.5 mg selenomethionine/kg diet) for 90 days. Se-rich basal diets were based on 0.2 mg/kg sodium selenite contained. Five hours before euthanized, 20 broilers were randomly selected from each group and given lipopolysaccharide (200 µg/kg BW) by intraperitoneal injection, Con+LPS group and Se+LPS group, respectively. The Con group and Se group were given equal saline by intraperitoneal injection. We observed the microscopic pathological changes of liver tissue detected oxidative stress by kit and detected the expression of inflammatory factors, heat shock protein (HSP), and nod-like receptor protein 3 (NLRP3)-related genes by qRT-PCR and Western blot. With the microscope, we found the Con+LPS group had obvious inflammatory lesions such as sinusoidal congestion, but the damage was significantly alleviated in the Se+LPS group. In the Con+LPS group, the activity of GSH-Px and the content of GSH were significantly decreased compared with those in the Con group; however, they are increased in the Se group and in the Se + LPS group. Inflammatory factors (MyD88, NF-κB, TNF-α, IL-1ß, IL-6, IL-12, IL-18, iNOS, and COX-2), heat shock proteins (HSP27, HSP60, HSP70, and HSP90), and the expression of NLRP3 and caspase-1 increased in the Con+LPS group compared with those in the Con group, while they were lower in the Se+LPS group than in the Con+LPS group. We concluded that selenomethionine inhibits the LPS-induced inflammation of liver tissue via suppressing the TLR4-NF-κB-NLRP3 signaling pathway.

Selenomethionine alleviates LPS-induced chicken myocardial inflammation by regulating the miR-128-3p-p38 MAPK axis and oxidative stress.

Selenium is closely related to the occurrence of heart disease, and an appropriate amount of selenium can alleviate inflammatory changes caused by various factors. Lipopolysaccharide (LPS), as a specific component of the cell wall of Gram-negative bacteria, is often used to construct various inflammatory models. In order to explore the effect of selenium on LPS-induced myocardial inflammation in chickens, we chose 4-month-old laying hens to be fed with a selenium-rich diet containing 0.5 g kg-1 Se, and injected LPS into the abdominal cavity at the age of 8 months to establish an inflammation model. We observed the myocardial tissue lesions by light microscopy, and detected miR-128-3p, p38MAPK, and NF-κB pathway-associated inflammatory factors and Th1/Th2 related factors by qRT-PCR and Western blot. The results showed that LPS stimulation inhibited miR-128-3p, which increased the expression of p38MAPK and NF-κB, while the expression of TNF-α, IL-1, PTGE, COX-2 and iNOS increased. Additionally, the expression of IL-4 and IL-6 increased and IFN-γ decreased, suggesting an imbalance of Th1/Th2. We also found that LPS treatment not only increased the content of H2O2 and MDA in the myocardium, but also increased the expression of HSP60, HSP70 and HSP90, while the activity of SOD, GPX and CAT and the content of GSH decreased. Interestingly, the addition of selenium can alleviate the changes in the above indicators. Finally, we concluded that selenium inhibits the occurrence of oxidative stress and ultimately alleviates myocardial inflammation induced by LPS through the miR-128-3p-p38MAPK-NF-κB pathway.