Assessing the neurotoxicity of airborne nano-scale particulate matter in human iPSC-derived neurons using a transcriptomics benchmark dose model.

Airborne nano-scale particulate matter (nPM) exposure is a risk factor for neurological diseases. However, to date, there has been no comprehensive evaluation of ambient nPM's neurotoxicity. We examined the toxic effects of nPM on human neurons derived from induced pluripotent stem cells (iPSCs) at doses ranging from 0 to 200 µg/mL, and employed whole-genome RNA-sequencing in different dose groups to gain further insight into the neurotoxicity of ambient nPM. Our findings showed that nPM was absorbed by neurons, and induced a variety of toxic effects. The apical benchmark dose lower confidence bound (aBMDL) values of each effect endpoint were ranked as follows, in ascending order: mitochondrial membrane potential, neurite length, early apoptosis, cell viability. BMD analysis based on transcriptomic data revealed that the point of departure (PoD) of the 20 pathways with the lowest p-values (0.75 µg/mL), the top 20 upstream regulators (0.79 µg/mL) and the neurological diseases (0.77 µg/mL) could be appropriate for nPM neurotoxicity evaluation. The transcriptomic PoDs (tPoDs) were similar to apical PoDs (aPoDs) since their absolute fold differences were within 10-fold. Further analysis of the transcriptomic data revealed that nPM exposure could disturb the pathways related to ferroptosis, neurotransmitters, xenobiotic metabolism, etc., which might be critical in regulating nPM neurotoxicity. We also found that low-dose nPM induced cytokine signaling pathways, while high doses of nPM activated cell-cycle regulation and DNA repair pathways. Our results indicate that BMD modeling based on transcriptomic data could be useful in illustrating the neurotoxic mechanism, and also could be a promising method for evaluating the potential health risks of nPM.

An aqueous extract of Prunella vulgaris L. inhibits the growth of papillary thyroid carcinoma by inducing autophagy in vivo and in vitro.

The continued global rise in papillary thyroid carcinoma (PTC) combined with potential adverse effects of regular treatments calls for an alternative therapy. Prunella vulgaris L. (PV) is commonly used as a herbal remedy for thyroid diseases in China, but its influence on PTC is unclear. This study investigated the effect of PV aqueous extract on PTC and its underlying mechanism using a mouse xenograft model and the human PTC cell line K1. PV suppressed tumor growth in PTC-bearing mice at 0.05 and 0.1 g/kg bw, accompanied by improvements in autophagy-related protein expressions in xenografts. In K1 cells, PV inhibited cell growth and induced autophagic flux, manifesting as changes in autophagy-related proteins, the presence of autophagosomes, and a further increase in LC3-II by co-incubation with bafilomycin A1. Autophagy inhibitor 3-methyladenine ameliorated the autophagic cell death caused by PV. The mammalian target of rapamycin (mTOR) activator MHY1485 blocked the antiproliferative activity of PV by regulating mTOR, unc-51-like autophagy activating kinase 1 (ULK1), autophagosomes formation, and autophagy-related proteins. The adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C attenuated PV-induced inhibition of mTOR. Our results suggest that PV inhibits the growth of PTC in vivo and in vitro via autophagy, which is associated with the AMPK/mTOR/ULK1 pathway. Thus, PV has the potential to function as a therapeutic agent against PTC.

Influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters in petrochemical workers: a cross-sectional study.

BACKGROUND: Ubiquitously distributed benzene is a known hematotoxin. Increasing evidence has suggested that erythroid-related hematologic parameters may be sensitive to benzene exposure. Fat content, which is also closely associated with erythroid-related hematologic parameters, may affect the distribution and/or metabolism of benzene, and eventually benzene-induced toxicity. METHODS: To explore the influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters, we recruited 1669 petrochemical workers and measured their urinary S-phenylmercapturic acid (SPMA) concentration and erythroid-related hematological parameters. Indices for fat content included body fat percentage (BF%), plasma total cholesterol (TC) and triglycerides (TG), and occurrence of fatty liver. RESULTS: The dose-response curve revealed U-shaped nonlinear relationships of SPMA with hematocrit (HCT) and mean corpuscular hemoglobin concentration (MCHC) (P-overall < 0.001, and P-nonlinear < 0.015), as well as positive linear associations and r-shaped nonlinear relationships of continuous fat content indices with erythroid-related hematological parameters (P-overall ≤0.005). We also observed modification effects of fat content on the associations between benzene exposure and erythroid-related hematological parameters, with workers of lower or higher BF% and TG more sensitive to benzene-induced elevation of MCHC (Pinteraction = 0.021) and benzene-induced decrease of HCT (Pinteraction = 0.050), respectively. We also found that some erythroid-related hematologic parameters differed between subgroups of workers with different SPMA levels and fat content combination. CONCLUSIONS: Our study suggested that benzene exposure, fat content, and their interactions may affect erythroid-related hematological parameters in petrochemical workers in a complex manner that are worthy of further investigation.

Conditionally reprogrammed human normal bronchial epithelial cells express comparable levels of cytochromes p450 and are sensitive to BaP induction.

Cytochromes p450 (CYPs) metabolize thousands of endogenous and exogenous chemicals, including toxic compounds and drugs. The primary cells have relative short life span and are not able to sustain levels of metabolic enzymes CYPs expression and activity long enough in vitro. The immortalized cell lines are also not ideal for toxicity testing because of their low levels of CYPs expression. In this study, we established human normal bronchial epithelial cells using conditional reprogramming (CR) technique from three human donors (named as CR-HNBE1-3). These CR cells can proliferate continuously in defined culture system over 50 PDs within 2 months. The CR-HNBE cells exhibited the normal diploid karyotype, normal response to DNA damage and normal differentiation potential under the matrigel 3D culture condition. The CR-HNBE cells express the basal epithelial marker cytokeratin 14 (CK14) and epithelial secretory marker Mucin 5AC. Most importantly, CR-HNBE cells express comparable levels of CYP1B1 and CYP2E1 as those in lung tissue. These CR cells also express comparable mRNA of CYP1A1/CYP1A2, CYP2B6/CYP2C9/CYP2D6 and CYP3A4/CYP3A5 compared to the lung tissue. The basal activity of CYP1A1/CYP1B1 in these CR cells was 3-6 folds higher than that of 16HBE cells (an immortalized cell line widely used in toxicology field). Our data also demonstrated that Benzo(a)pyrene (BaP) induced up to 100 folds of mRNA expression of CYP1A1 or CYP1A2 in CR-HNBE cells. The activity of CYP1A1/CYP1B1 was induced by BaP up to 7-8 folds in CR-HNBE cells, while the activity of CYP1A1/CYP1B1 was induced maximum 2.5 folds in 16HBE cells. Taken together, CR-HNBE cells express comparable levels of CYPs and are sensitive to BaP induction, and will serve a sensitive, physiological and valuable in vitro toxicity testing model. This is the first report that normal human airway cells can be propagated for a long time and maintain comparable levels of CYPs.

Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen-induced cell transformation.

Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen-induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p-H3S10) and Ser28 (p-H3S28) was upregulated by 1.5-4.8 folds and 2.1-4.3 folds, respectively in aflatoxin B1 -transformed hepatocytes L02 cells (L02RT-AFB1 ), benzo(a)pyrene-transformed HBE cells (HBERT-BaP), and coke oven emissions-transformed HBE cells (HBERT-COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage-independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p-H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen-induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p-H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB1 treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p-H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes.

Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes.

Induction of metallothionein (MT) expression is involved in metal homeostasis and detoxification. To identify the key pathways that regulate metal-induced cytotoxicity, we investigate how phosphorylated metal-responsive transcription factor-1 (MTF-1) contributed to induction of MT expression. Immortal human embryonic kidney cells (HEK cells) were treated with seven kinds of metals including cadmium chloride (CdCl2), zinc sulfate (ZnSO4), copper sulfate(CuSO4), lead acetate (PbAc), nickel sulfate (NiSO4), sodium arsenite (NaAsO2), and potassium bichromate (K2Cr2O7). The MT expression was induced in a dose-response and time-dependent manner upon various metal treatments. A cycle of phosphorylation and dephosphorylation was required for translocation of MTF-1 from cytoplasm to nucleus, leading to the up-regulation of MTs expression. Protein phosphatase 2A (PP2A) participated in regulating MT expression through dephosphorylation of MTF-1. A loss-of-function screen revealed that the specific PP2A complexes containing PR110 were involved in metal-induced MT expression. Suppression of PP2A PR110 in HEK cells resulted in the persistent MTF-1 phosphorylation and the disturbance of MTF-1 nuclear translocation, which was concomitant with a significant decrease of MT expression and enhanced cytotoxicity in HEK cells. Notably, MTF-1 was found in complex with specific PP2A complexes containing the PR110 subunit upon metal exposure. Furthermore, we identify that the dephosphorylation of MTF-1 at residue Thr-254 is directly regulated by PP2A PR110 complexes and responsible for MTF-1 activation. Taken together, these findings delineate a novel pathway that determines cytotoxicity in response to metal treatments and provide new insight into the role of PP2A in cellular stress response.

[The advance of model of action in low-dose chronic benzene exposure induced hematotoxicity].

Benzene is classified as Group 1 carcinogen by IARC. It has been found that benzene induces hematotoxicity even in low dose exposure. The identification of key events during benzene induced hematotoxicty leads to adjustment of occupational exposure limits of benzene. In this review, we focus on the exposure, metabolism, target organs, key epigenetic changes, toxicty effects and end points of low-dose chronic benzene exposure induced hematotoxicity and finally discuss the perspectives on the future study of this area.

REXO2 up-regulation is positively correlated with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

BACKGROUND: As a homologous counterpart to the prokaryotic oligonuclease found in the cellular cytoplasm and mitochondrion, REXO2 assumes a pivotal role in the maintenance of mitochondrial homeostasis. Nevertheless, the precise functions and mechanisms by which REXO2 operates within the context of hepatocellular carcinoma (HCC) have hitherto remained unexamined. METHODS: The expression levels of REXO2 in HCC tissues were evaluated through the utilization of the immunohistochemical (IHC) method, and subsequently, the association between REXO2 expression and the clinicopathological characteristics of HCC patients was scrutinized employing the χ2 test. A battery of experimental assays, encompassing CCK8 viability assessment, cell colony formation, wound healing, and transwell assays, were conducted with the aim of elucidating the biological role of REXO2 within HCC cells. Complementary bioinformatics analyses were undertaken to discern potential correlations between REXO2 and immune infiltration in tumor tissues. RESULTS: Our IHC findings have unveiled a notable up-regulation of REXO2 within HCC tissues, and this heightened expression bears the status of an independent prognostic factor, portending an adverse outcome for HCC patients (P < 0.05). Upon the attenuation of REXO2 expression, a discernible reduction in the rates of proliferation, invasion and migration of HCC cells ensued (P < 0.05). Furthermore, transcriptome sequencing analysis has provided insights into the putative influence of REXO2 on the development of HCC through the modulation of TNF and NF-κB signaling pathways. Additionally, our bioinformatics analyses have demonstrated a positive correlation between REXO2 and tumor immune cell infiltration, as well as immune checkpoint CTLA-4. CONCLUSIONS: In summation, our results posit an association between the up-regulation of REXO2 and adverse prognostic outcomes, alongside the involvement of immune-related signaling pathways and tumor immune infiltration within the realm of HCC.

Non-linear association and benchmark dose of blood pressure on carotid artery intima-media thickening in a general population of southern China.

Background and aims: This study aimed to evaluate whether there is a J-curve association between blood pressure (BP) and carotid artery intima-media thickening (CAIT) and estimate the effect of the turning point of BP on CAIT. Methods and results: Data from 111,494 regular physical examinations conducted on workers and retirees (aged 18 years or older) between January 2011 and December 2016, exported from the hospital information system, were analyzed. Restricted cubic splines (RCS) logistic regression was employed to access the association of BP with CAIT, and Bayesian benchmark dose methods were used to estimate the benchmark dose as the departure point of BP measurements. All the pnon-linear values of BP measurements were less than 0.05 in the RCS logistic regression models. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) had J-curve associations with the risk of CAIT at a turning point around 120/70 mmHg in the RCS. The benchmark dose for a 1% change in CAIT risk was estimated to be 120.64 mmHg for SBP and 72.46 mmHg for DBP. Conclusion: The J-curve associations between SBP and DBP and the risk of CAIT were observed in the general population in southern China, and the turning point of blood pressure for significantly reducing the risk of CAIT was estimated to be 120.64/72.46 mmHg for SBP/DBP.

Histone H3K36me3 mediates the genomic instability of Benzo[a]pyrene in human bronchial epithelial cells.

Histone modifications maintain genomic stability and orchestrate gene expression at the chromatin level. Benzo [a]pyrene (BaP) is the ubiquitous carcinogen widely spread in the environment, but the role and regulatory mechanism of histone modification in its toxic effects remain largely undefined. In this study, we found a dose-dependent reduction of histone H3 methylations at lysine4, lysine9, lysine27, lysine36 in HBE cells treated with BaP. We observed that inhibiting H3K27 and H3K36 methylation impaired cell proliferation, whereas the loss of H3K4, H3K9, H3K27, and H3K36 methylation led to increased genomic instability and delayed DNA repair. H3K36 mutation at both H3.1 and H3.3 exhibited the most significant impacts. In addition, we found that the expression of SET domain containing 2 (SETD2), the unique methyltransferase catalyzed H3K36me3, was downregulated by BaP dose-dependently in vitro and in vivo. Knockdown of SETD2 aggravated DNA damage of BaP exposure, which was consistent with the effects of H3K36 mutation. With the aid of chromatin immunoprecipitation (ChIP) -seq and RNA-seq, we found that H3K36me3 was responsible for transcriptional regulation of genes involved in pathways related to cell survival, lung cancer, metabolism and inflammation. The enhanced enrichment of H3K36me3 in genes (CYP1A1, ALDH1A3, ACOXL, WNT5A, WNT7A, RUNX2, IL1R2) was positively correlated with their expression levels, while the reduction of H3K36me3 distribution in genes (PPARGC1A, PDE4D, GAS1, RNF19A, KSR1) were in accordance with the downregulation of gene expression. Taken together, our findings emphasize the critical roles and mechanisms of histone lysine methylation in mediating cellular homeostasis during BaP exposure.

Comprehensive analysis of the protein phosphatase 2A regulatory subunit B56ε in pan-cancer and its role and mechanism in hepatocellular carcinoma.

BACKGROUND: B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear. AIM: To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells. RESULTS: In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all P < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all P < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all P < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells. CONCLUSION: B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.

Current Opinions on the Relationship Between CMTM Family and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a typically malignant tumor in the digestive system. The mortality of HCC ranks third place in the world, second only to lung cancer and colorectal cancer. For the characteristics of high invasiveness, high metastasis, high recurrence rate as well as short survival time, HCC treatment has always been difficult in clinical practice. Many causes have contributed to the appearance of these features, including insidious onset, high degree of malignancy, lack of effective early molecular diagnostic markers, and disease prediction models. The human chemokine-like factor superfamily (CMTMs) is a new gene family consisting of CKLF and CMTM1-CMTM8. CMTMs have a marvel domain which can activate and chemotaxis immune cells. Many studies have reported that CMTMs are involved in the regulation of cell growth and development, and play an important role in the malignant progression of the immune system and reproductive system, especially in the development of tumors. In this review, we summarized the structure and function of the human CMTMs, the relationship between its family members and HCC, the prognostic value, potential functions, and mechanisms in HCC. CMTMs could provide a new diagnostic and therapeutic target in clinical practice for patients with HCC.

Migrasomes and tetraspanins in hepatocellular carcinoma: current status and future prospects.

In recent years, many studies have attempted to clarify the formation, structure and biological function of migrasomes, which are defined as specialized organelles formed by the tips and intersections of Retraction Fibrils during cell migration. It has confirmed that migrasomes were involved in various critical biological processes and diseases, and has became a new research hotspot. In this paper, we reviewed the formation and biological functions of migrasomes, explored the relationship between migrasomes, tetraspanins and hepatocellular carcinoma and discussed the potential applications of migrasomes in hepatocellular carcinoma.

Migrasomes are specialized parts of the cell that are responsible for transporting proteins and molecules to their designated cellular locations. In this review, we have attempted to understand their formation, structure and biological function. We have also discussed the potential applications of migrasomes in liver cancer. Our study concluded that more research is required for a better understanding of migrasomes and their contents in liver cancer.

Bioinformatics analysis of key genes and potential mechanism in cadmium-induced breast cancer progression.

Cadmium (Cd) may be associated with breast cancer progression, but the detailed molecular mechanism has not been fully elucidated. In this study, one public dataset (GSE136595) was used to identify differentially expressed genes (DEGs) in Cd-treated MCF-7 breast cancer cells. We determined a total of 2077 DEGs, and Ingenuity Pathway Analysis (IPA) software showed that 246 of them were related to tumor progression. Pathway analysis of these DEGs indicated that the HIF1α signaling and the epithelial-mesenchymal transition (EMT) pathway regulated by growth factors might be activated. Moreover, twist family bHLH transcription factor 1 (TWIST1), lysine demethylase 3A (KDM3A), Kruppel-like factor 4 (KLF4), nuclear protein 1 (NUPR1), neurogenin 3 (NEUROG3), and HNF1 homeobox B (HNF1B) might be the key transcription factors. And the result of protein-protein interaction (PPI) analysis showed that the hub genes in these 246 DEGs were tumor protein p53 (TP53), polo-like kinase 1 (PLK1), sirtuin 1 (SIRT1), protein tyrosine phosphatase non-receptor type 11 (PTPN11), caspase 8 (CASP8), cyclin-dependent kinase 6 (CDK6), calmodulin 3 (CALM3), KRAS proto-oncogene (KRAS), extra spindle pole bodies like 1 (ESPL1), and marker of proliferation Ki-67 (MKI67). Further analysis indicated that TWIST1, NUPR1, KRAS, and PTPN11 were related to the prognostic of breast cancer based on the Cancer Genome Atlas (TCGA) and they were validated to be upregulated in the Cd-treated MCF-7 cells. Our results suggested that the HIF1α signaling and the EMT pathway regulated by growth factors might be participant in the Cd-induced breast cancer progression and TWIST1, NUPR1, KRAS, and PTPN11 might be potential key genes.

Weighted Gene Co-Expression Network Analysis (WGCNA) Reveals the Functions of Syndecan-1 to Regulate Immune Infiltration by Influenced T Cells in Glioma.

Our previous studies shown that syndecan-1 (SDC1) may be a novel class of biomarkers for the diagnosis and treatment of glioma, but its specific roles and the in-depth molecular mechanism remain elusive. Here, we used Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithms and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms to evaluate the immune score of tumor samples and quantify the relative infiltration of immune cells in the tumor microenvironment (TME), respectively, in different data sets obtained from the Chinese Glioma Genome Atlas and The Cancer Gene Atlas. Next, we calculate the correlation of the immune score and immune cells with SDC1, respectively. To identify the specific process regulated by SDC1, the differentially expressed genes (DEGs) analysis between the high and low expression of SDC1 of glioma samples were used to discover the hub genes through Weighted Gene Coexpression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed cardinal biological processes and pathways involved in genes and tumor grade correlation and survival analysis verified its significance in glioma. The results show that SDC1 is associated with the immune infiltration of glioma in the TME, especially activated CD4+T cells and CD8+T cells. The three data sets filter 8,887 DEGs, the genes in the blue modules were selected as hub genes in WGCNA. GO and KEGG analysis found eight genes in the blue modules involved in antigen processing and presentation in T cells in glioma. Kaplan-Meier estimator and log-rank test statistic determined that the introduced genes are associated with poor prognosis in glioma. Protein-protein network interaction analysis showed that SDC1 may regulate antigen processing and presentation through CTSL or CD4 in glioma. Finally, this study provided insights and clues for the next research direction of SDC1 and identified the key pathways and genes that might participate in the immune escape of glioma. These results might provide a new insight on the study of immune infiltration of glioma in the future.

Quantitative structure-activity relationship models for genotoxicity prediction based on combination evaluation strategies for toxicological alternative experiments.

Mutagenicity exerts adverse effects on humans. Conventional methods cannot simultaneously predict the toxicity of a large number of compounds. Most mutagenicity prediction models are based on a single experimental type and lack other experimental combination data as support, resulting in limited application scope and predictive ability. In this study, we partitioned data from GENE-TOX, CPDB, and Chemical Carcinogenesis Research Information System according to the weight-of-evidence method for modelling. In our data set, in vivo and in vitro experiments in groups as well as prokaryotic and eukaryotic cell experiments were included in accordance with the ICH guideline. We compared the two experimental combinations mentioned in the weight-of-evidence method and reintegrated the experimental data into three groups. Nine sub-models and three fusion models were established using random forest (RF), support vector machine (SVM), and back propagation (BP) neural network algorithms. When fusing base models under the same algorithm according to the ensemble rules, all models showed excellent predictive performance. The RF, SVM, and BP fusion models reached a prediction accuracy rate of 83.4%, 80.5%, 79.0% respectively. The area under the curve (AUC) reached 0.853, 0.897, 0.865 respectively. Therefore, the established fusion QSAR models can serve as an early warning system for mutagenicity of compounds.

Global H3K79 di-methylation mediates DNA damage response to PAH exposure in Chinese coke oven workers.

Polycyclic aromatic hydrocarbons (PAHs) are the main contaminants of coke oven emissions which can induce serious genetic damage in coke oven workers. Epigenetic alternations play essential roles in the regulation of DNA damage effect of PAHs. Previous studies indicate that H3K79 di-methylation (H3K79me2) is integral in DNA damage repair. However, the potential role of H3K79me2 in DNA damage response (DDR) following PAHs exposure is still unclear. In this study, we recruited 256 male coke oven workers and control workers, and examined H3K79me2 and DNA damage in their peripheral blood lymphocytes (PBLCs). The results showed that global H3K79me2 of coke oven workers was 29.3% less than that of the controls (P < 0.001). The H3K79me2 was negatively correlated with the concentration of urinary 1-hydroxypyrene (1-OHP) (ß = -0.235, P < 0.001) and level of genetic damage evaluated by comet assay (ßTail DNA % = -0.313, P < 0.001; ßOTM = -0.251, P = 0.008). Consistently, we found that benzo(a)pyrene (BaP) inhibited H3K79me2 in immortalized human bronchial epithelial (HBE) cells in a time-dependent manner. In order to explore the function of H3K79me2 in PAHs DDR, we established histone 3.1/3.3 K79A mutant cells (H3K79 A) to suppress H3K79me2. H3K79 A cells showed more serious DNA damage and decreased cell viability than control cells after BaP treatment. In addition, we also found that the expression of DOT1L, the only methyltransferase in H3K79, was repressed by BaP dose-dependently. DOT1L knockdown resulted in decreased H3K79me2 level and aggravated DNA damage after BaP exposure. This suggests that BaP induces H3K79me2 repression via inhibiting DOT1L expression. In conclusion, these findings indicate that PAH exposure decreases the level of global H3K79me2, which is integral for DNA damage response regulation of PAHs.

Association between H3K36me3 modification and methylation of LINE-1 and MGMT in peripheral blood lymphocytes of PAH-exposed workers.

To explore the epigenetic alterations in response to DNA damage following polycyclic aromatic hydrocarbons (PAHs) exposure and the crosstalk between different epigenetic regulations, we examined trimethylated Lys 36 of histone H3 (H3K36me3) and methylation of 'long interspersed element-1 (LINE-1)' and 'O 6-methylguanine-DNA methyltransferase (MGMT)' in peripheral blood lymphocytes (PBLCs) of 173 coke oven workers (PAH-exposed group) and 94 non-exposed workers (control group). The PAH-exposed group showed higher internal PAH exposure level, enhanced DNA damage and increased MGMT expression (all P < 0.001). Notably, the methylation of LINE-1 and MGMT decreased by 3.9 and 40.8%, respectively, while H3K36me3 level was 1.7 times higher in PBLCs of PAH-exposed group compared to control group (all P < 0.001). These three epigenetic marks were significantly associated with DNA damage degree (all P < 0.001) and PAH exposure level in a dose-response manner (all P < 0.001). LINE-1 hypomethylation is correlated with enhanced H3K36me3 modification (ß = -0.198, P = 0.002), indicating a synergistic effect between histone modification and DNA methylation at the whole genome level. In addition, MGMT expression was positively correlated with H3K36me3 modification (r = 0.253, P < 0.001), but not negatively correlated with MGMT methylation (r = 0.202, P < 0.05). The in vitro study using human bronchial epithelial cells treated with the organic extract of coke oven emissions confirmed that H3K36me3 is important for MGMT expression following PAH exposure. In summary, our study indicates that histone modification and DNA methylation might have synergistic effects on DNA damage induced by PAH exposure at the whole genome level and H3K36me3 is more essential for MGMT expression during the course.

Critical appraisal of clinical practice guidelines for the diagnosis and treatment of stress urinary incontinence using AGREE II instrument: a systematic review protocol.

INTRODUCTION: Stress urinary incontinence is a major health problem, and several clinical guidelines have been formulated and released regarding this in different countries. However, the recommendations in these guidelines formulated by different organisations and countries are inconsistent. This review aims to conduct a critical appraisal of clinical practice guidelines for the diagnosis and treatment of stress urinary incontinence. METHODS AND ANALYSIS: We will conduct a comprehensive search in the following databases: PubMed, Embase, Medline, Cochrane Library, three Chinese databases and six guideline databases. The databases will be searched from January 2003, and the comprehensive search will be done again to include all the qualified guidelines before making conclusions. The quality of clinical practice guidelines will be assessed by three appraisers using the Appraisal of Guidelines Research and Evaluation II instrument, and this will be scored. The recommendation available in the guidance will also be summarised in different domains including the diagnosis standard, recommended examination and questionnaire for assessment, conservative treatment and surgical treatment. ETHICS AND DISSEMINATION: This review will be disseminated through peer-reviewed publications. The results will help inform the health practitioners about the recommendations in clinical practice guidelines. PROSPERO REGISTRATION NUMBER: CRD42018115743.

Enhanced H3K4me3 modifications are involved in the transactivation of DNA damage responsive genes in workers exposed to low-level benzene.

In this study, we explore whether altered global histone modifications respond to low-level benzene exposure as well as their association with the hematotoxicity. We recruited 147 low-level benzene-exposed workers and 122 control workers from a petrochemical factory in Maoming City, Guangdong Province, China. The internal exposure marker level, urinary S-phenylmercapturic acid (SPMA), in benzene-exposed workers was 1.81-fold higher than that of the controls (P < 0.001). ELISA method was established to examine the specific histone modifications in human peripheral blood lymphocytes (PBLCs) of workers. A decrease in the counts of white blood cells (WBC), neutrophils, lymphocytes, and monocytes appeared in the benzene-exposed group (all P < 0.05) compared to the control group. Global trimethylated histone 3 lysine 4 (H3K4me3) modification was enhanced in the benzene-exposed group (P < 0.05) and was positively associated with the concentration of urinary SPMA (ß = 0.103, P = 0.045) and the extent of DNA damage (% Tail DNA: ß = 0.181, P = 0.022), but was negatively associated with the leukocyte count (WBC: ß = -0.038, P = 0.023). The in vitro study revealed that H3K4me3 mark was enriched in the promoters of several DNA damage responsive (DDR) genes including CRY1, ERCC2, and TP53 in primary human lymphocytes treated with hydroquinone. Particularly, H3K4me3 modification was positively correlated with the expression of CRY1 in the PBLCs of benzene-exposed workers. These observations indicate that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene exposure.