Proteomics analysis of plasm exosomes in early pregnancy among normal pregnant women and those with antiphospholipid syndrome.

Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder associated with thrombosis and adverse obstetric outcomes. Early diagnosis and intervention can improve pregnancy outcomes to some extent, but current results are unsatisfactory. Exosomes, containing biomacromolecules relevant to reproduction, play essential roles in pregnancy. However, research progress on their involvement in APS remains limited. Objectives: This study aims to investigate protein profile changes in plasma exosomes and identify potential biomarkers for obstetric APS. Methods: We employed tandem mass tag (TMT) markers to analyze exosome protein profiles from 6 healthy early pregnant women and 6 early-stage APS patients. Quantitative proteomics analysis was conducted using the Maxquant search engine. Results: Differential expression analysis identified 51 upregulated and 22 downregulated proteins in plasma exosomes from early pregnant women with APS, such as serpin peptidase inhibitor C1/A1/A7, apolipoprotein 1/2, orosomucoid 1/2 and apolipoprotein H. Kyoto Encyclopedia of Genes and Genomes analysis shows that differentially expressed proteins are enriched in the PPAR signaling pathway and staphylococcus aureus infection pathway. Enrichment analysis indicated associations with glycerolipid biosynthesis, vitamin transport, and negative regulation of very-low-density lipoprotein particle remodeling. Conclusion: Our study highlights alterations in the protein profiles of plasma exosomes in APS pregnant patients and proposes potential biomarkers, offering insights for early diagnosis and treatment and improving reproductive outcomes.

Single-Cell Transcriptome Analysis of Small Cell Neuroendocrine Carcinoma of the Endometrium Reveals ISL1 as a Potential Biomarker for Diagnosis and Treatment.

BACKGROUND: As a dedifferentiated tumor, small cell endometrial neuroendocrine tumors (NETs) are rare and frequently diagnosed at an advanced stage with a poor prognosis. Current treatment recommendations are often extrapolated from histologically similar tumors in other sites or based on retrospective studies. The exploration for diagnostic and therapeutic markers in small cell NETs is of great significance. METHODS: In this study, we conducted single-cell RNA sequencing on a specimen obtained from a patient diagnosed with small cell endometrial neuroendocrine carcinoma (SCNEC) based on pathology. We revealed the cell map and intratumoral heterogeneity of the cancer cells through data analysis. Further, we validated the function of ISL LIM Homeobox 1 (ISL1) in vitro in an established neuroendocrine cell line. Finally, we examined the association between ISL1 and tumor staging in small cell lung cancer (SCLC) patient samples. RESULTS: We observed the significant upregulation of ISL1 expression in tumor cells that showed high expression of the neuroepithelial markers. Additionally, in vitro cell function experiments demonstrated that the high ISL1 expression group exhibited markedly higher cell proliferation and migration abilities compared to the low expression group. Finally, we showed that the expression level of ISL1 was correlated with SCLC stages. CONCLUSIONS: ISL1 protein in NETs shows promise as a potential biomarker for diagnosis and treatment.

Possible contributions of fibrogenesis to recurrent miscarriages - A transcriptome analysis.

Recurrent miscarriages (RM) generally refer to two or more consecutive pregnancy losses. The risk of miscarriages grows with its frequency of occurrences, so as the future obstetric complications or longer-term health problems for patients. Most previous researches sought to discover the etiology of RM by making comparisons between patients with RM and fertile women. Our study collected decidua tissues from patients with RM and single miscarriage (SM) for transcriptome sequencing analysis and aimed at identifying vital factors contributing to additional miscarriages after previous miscarriage. Between the RM and SM group, a total of 122 differentially expressed genes (DEGs) were detected and pathways associated with cell adhesion and ECM remodeling were particularly enriched in the RM group, which indicated abnormally activated fibrogenesis process. Particularly, the enhancement of ITGB6, EGFLAM and COL3A1 in the RM group were validated by RT-qPCR. Our study discovered that fibrogenesis, which might be caused by intrauterine manipulation, could lead to recurrent miscarriages after a previous miscarriage. Therefore, we encourage higher attention to thorough prevention and prompt remedies towards fibrotic disorders related diseases.

Review on novel toxicological effects and personalized health hazard in workers exposed to low doses of benzene.

Several recent reports indicate health hazards for workers with below occupational limit exposure to benzene (BZ). Our updated review indicates that such low exposures induced traditional as well as novel toxicity/genotoxicity, e.g., increased mitochondria copy numbers, prolongation of telomeres, impairment of DNA damage repair response (DDRR), perturbations of expression in non-coding RNAs, and epigenetic changes. These abnormalities were associated with alterations of gene expression and cellular signaling pathways which affected hematopoietic cell development, expression of apoptosis, autophagy, etc. The overarching mechanisms for induction of health risk are impaired DDRR, inhibition of tumor suppressor genes, and changes of MDM2-p53 axis activities that contribute to perturbed control for cancer pathways. Evaluation of the unusual dose-responses to BZ exposure indicates cellular over-compensation and reprogramming to overcome toxicity and to promote survival. However, these abnormal mechanisms also promote the induction of leukemia. Further investigations indicate that the current exposure limits for workers to BZ are unacceptable. Based on these studies, the new exposure limits should be less than 0.07 ppm rather than the current 1 ppm. This review also emphasizes the need to conduct appropriate bioassays, and to provide more reliable decisions on health hazards as well as on exposure limits for workers. In addition, it is important to use scientific data to provide significantly improved risk assessment, i.e., shifting from a population- to an individual-based risk assessment.

The Sweet Potato K+ Transporter IbHAK11 Regulates K+ Deficiency and High Salinity Stress Tolerance by Maintaining Positive Ion Homeostasis.

The K+ transporter KT/HAK/KUP (K+ transporter/high-affinity K+/K+ uptake) family has a critical effect on K+ uptake and translocation in plants under different environmental conditions. However, the functional analysis of KT/HAK/KUP members in sweet potatoes is still limited. The present work reported the physiological activity of a new gene, IbHAK11, in the KT/HAK/KUP family in sweet potatoes. IbHAK11 expression increased significantly in the low K+-tolerant line compared with the low K+-sensitive line following treatment with low K+ concentrations. IbHAK11 upregulation promoted root growth in Arabidopsis under low K+ conditions. Under high saline stress, transgenic lines had superior growth and photosynthetic characteristics compared with the wild-type (WT). As for IbHAK11-overexpressing plants, activation of both the non-enzymatic and enzymatic reactive oxygen species (ROS) scavenging systems was observed. Therefore, IbHAK11-overexpressing plants had lower malondialdehyde (MDA) and ROS levels (including H2O2 and O2-) compared with WT under salt-induced stress. We also found that under both low K+ and high salinity conditions, overexpression of IbHAK11 enhanced K+ translocation from the root to the shoot and decreased Na+ absorption in Arabidopsis. Consequently, IbHAK11 positively regulated K+ deficiency and high salinity stresses by regulating K+ translocation and Na+ uptake, thus maintaining K+/Na+ homeostasis in plants.

Benchmark dose estimation for benzene-exposed workers in China: Based on quantitative and multi-endpoint genotoxicity assessments.

Based on previous exposure studies, benzene (BZ) has been classified as a human carcinogen and occupational exposure limit (OELs) for BZ has been set to be about 1 ppm around the world. However, health hazards have still been reported with exposure below the OEL. Thus, the OEL needs to be updated to reduce health risk. The overall aim of our study was therefore to generate new OEL for BZ via a benchmark dose (BMD) approach and based on quantitative and multi-endpoint genotoxicity assessments. Genotoxicities were determined using the novel human PIG-A gene mutation assay, the micronucleus (MN) test and the COMET assay in benzene-exposed workers. Among the 104 workers with below current OELs, they exhibited significantly higher PIG-A mutant frequencies (MFs) (15.96 ± 14.41 × 10-6) and MN frequencies (11.55 ± 6.83‰) than those among the controls (PIG-A MFs: 5.46 ± 4.56 × 10-6, MN frequencies: 4.51 ± 1.58 ‰), but no difference in the COMET assay. A significant association was also observed between BZ exposure doses and PIG-A MFs and MN frequencies (P < 0.001). Our results indicate that health hazards were induced among workers with below OEL exposures. Based on results from the PIG-A and MN assays, the lower confidence limit of the BMD (BMDL) were calculated to be 8.71 mg/m3-year and 0.44 mg/m3-year, respectively. Based on these calculations, the OEL for BZ was determined to be lower than 0.07 ppm. This value can be considered by regulatory agencies to set new exposure limits and to better protect workers.

Efficient degradation of norfloxacin using a novel biochar-supported CuO/Fe3O4 combined with peroxydisulfate: Insights into enhanced contribution of nonradical pathway.

Nonradical persulfate oxidation techniques have evolved as a new contaminated water treatment approach due to its great tolerance to water matrixes. The catalysts of CuO-based composites have received much attention in that aside from SO4•-/•OH radicals, the nonradicals of singlet oxygen (1O2) can be also generated during persulfate activation via CuO. However, the issues regarding particles aggregation and metal leaching from the catalysts during the decontamination process remain to be addressed, which could have a remarkable impact on the catalytic degradation of organic pollutants. Accordingly in the present study, a novel biochar-supported bimetallic Fe3O4-CuO catalyst (CuFeBC) was facilely developed to activate peroxodisulfate (PDS) for the degradation of norfloxacin (NOR) in aqueous solution. The results showed CuFeBC has a superior stability against metal ions Cu/Fe leaching, and NOR (30 mg L-1) was degraded at 94.5% within 180 min in the presence of CuFeBC (0.5 g L-1) and PDS (6 mM) in pH 8.5. The scavenging of reactive oxygen species and electron spin resonance analysis revealed that 1O2 dominated the degradation of NOR. Compared with pristine CuO-Fe3O4, the interaction between biochar substrate and metal particles could significantly enhance the contribution of the nonradical pathway to NOR degradation from 49.6% to 84.7%. Biochar substrate could efficiently reduce the leaching of metal species from the catalyst, thereby maintaining excellent catalytic activity and lasting reusability of the catalyst. These findings could enlighten new insights into fine-tuning radical/nonradical processes from CuO-based catalysts for the efficient remediation of organic contaminants in polluted water.

Associations between DNA methylation and genotoxicity among lead-exposed workers in China.

Studies have shown that lead (Pb) exposure caused genotoxicity, however, the underlying mechanisms remain unclear. A mechanism may be via DNA methylation which is one of the most widely studied epigenetic regulations for cellular activities. Whether this is involved in Pb-induced genotoxicity has rarely been studied. Our study aimed to examine whether DNA methylation was associated with Pb exposure and genotoxicity, and to explore its potential mediating roles. A total of 250 Pb-exposed workers were enrolled. Blood lead levels (BLLs) and genotoxic biomarkers (Micronuclei and Comet) were analyzed. Methylation levels at CpG sites of LINE1 and Alu and promoter region of P53, BRCA1, TRIM36 and OGG1 were measured by pyrosequencing. Generalized linear model (GLM) combined with restricted cubic splines (RCS) were used to analyze relationships between Pb exposure, DNA methylation and genotoxicity. Mediation effect was used to explore mediating roles of DNA methylation. The distribution of BLLs was right-skewed and showed wide ranges from 23.7 to 636.2 µg/L with median (P25, P75) being 218.4 (106.1, 313.9) µg/L among all workers. Micronuclei frequencies showed Poisson distribution [1.94 ± 1.88‰] and Comet tail intensity showed normal distribution [1.69 ± 0.93%]. GLM combined with RCS showed that Alu methylation was negatively associated with BLLs, while P53 and OGG1 methylation were positively associated with BLLs. Micronuclei were negatively associated with Alu and TRIM36 methylation but positively with P53 methylation. Comet was positively associated with P53 and BRCA1 methylation. Mediation effect showed that Alu methylation mediated 7% effects on association between Pb exposure and micronuclei, whereas, P53 methylation mediated 14% and BRCA1 mediated 9% effects on association between Pb exposure and Comet. Our data show that Pb exposure induced changes of global and gene-specific DNA methylation which mediated Pb-induced genotoxicity.

A multiple and comprehensive approach to assess health risk in amalgam-exposed Chinese workers.

Fluorescent lamp manufacturing workers have been extensively exposed to mercury (Hg). Our aim was to assess their health risks using several approved occupational health risk assessment methods, and to find out which method was more suitable for identification of occupational health risks. Work locations, and air and urine samples were collected from 530 exposed workers in Zhejiang, China. Based on the calculated exposure doses, health risks and risk ratios (RRs) as health risk indices, were evaluated using: Environmental Protection Agency (EPA), Australian, Romanian, Singaporean, International Council on Mining and Metals (ICMM), and Control of Substances Hazardous to Health (COSHH) methods. Among the workers, 86.0% had higher Hg levels than the Chinese occupational exposure limits of 0.02 mg/m3, and 16.7% urine samples were higher than the biological exposure limits of 35.0 µg/g·creatinine. Among workers at the injection, etc. locations, their average RRs, evaluated by the EPA, COSHH and Singaporean methods were 0.97, 0.76, and 0.60, respectively, and were significantly higher than the ICMM (0.39), Australian (0.30) and Romanian (0.29) methods. The RRs from the Singaporean method showed significant correlations with the urinary Hg levels (P < 0.01). In conclusion, the Singaporean method was more appropriate than the others for health risk evaluation because the excessive risks were significantly associated with urinary Hg levels among the workers.

Epidemiological characteristics of hearing loss associated with noise temporal structure among manufacturing workers.

Objective: This study aimed to investigate the epidemiological characteristics of occupational noise-induced hearing loss (NIHL) among manufacturing workers, and to provide evidence for diagnosing and preventing occupational hearing loss caused by complex noise, which is different from Gaussian noise in temporal structure. Methods: One thousand and fifty manufacturing workers exposed to occupational noise were recruited in a cross-sectional survey. Exposure characteristics and epidemiological distribution of hearing loss and noise exposure metrics (noise energy and kurtosis) were investigated, and the relationship between noise exposure and hearing loss was analyzed. The effects of kurtosis on hearing threshold shift across different frequencies and on NIHL development with exposure duration and noise intensity were also investigated. Results: Each type of work had specific noise exposure metrics. Noise intensity and kurtosis were independent parameters (r = -0.004, p = 0.885). The prevalence of NIHL and the hearing threshold level had a specific distribution in different types of work. Kurtosis deepened the hearing notch at high frequencies and accelerated the formation of early hearing loss. The effect of exposure duration and noise intensity on the prevalence of high-frequency NIHL (i.e., at 3, 4, 6, and 8 kHz) for manufacturing workers increased with kurtosis in workers with noise exposure duration of less than 10 years and with LAeq.8h between 80 and 90 dB(A). Male (OR = 1.557, 95%CI = 1.141-2.124), age (OR = 1.033, 95%CI = 1.014-1.052), exposure duration (OR = 1.072, 95%CI = 1.038-1.107), kurtosis (OR = 1.002, 95%CI = 1.001-1.003), and noise intensity (LAeq.8h; OR = 1.064, 95%CI = 1.044-1.084) were risk factors for high-frequency NIHL. The speech-frequency NIHL (i.e., at 0.5, 1, and 2 kHz) risk of workers exposed to manufacturing noise was related to age (OR = 1.071, 95%CI = 1.043-1.100). There were no statistically significant associations between speech-frequency NIHL and sex, noise exposure duration, kurtosis, and noise intensity (LAeq.8h). Conclusion: The high-frequency NIHL prevalence among manufacturing workers is associated with sex, age, exposure duration, noise intensity, and temporal structure of noise, while the speech-frequency NIHL prevalence is associated with age. Kurtosis strengthens the association of noise exposure duration and noise intensity with high-frequency hearing loss. The influence of noise temporal structure should be considered in the diagnosis and early prevention of occupational hearing loss caused by complex noise.

Lymphocyte-based challenge DNA-repair assays for personalized health risk assessment.

Combinations of genetic and environmental factors are responsible for the development of many human diseases, such as cancer, as demonstrated using various biomarkers. Within this scenario, DNA repair holds a gate-keeper position which determines outcomes after appearance of DNA damage and, therefore, adverse cellular consequences, e.g., initiation of carcinogenesis. DNA repair deficiency and some of the subsequent events can be validated from studies using live cells from cancer patients. However, these deficiencies/events are difficult to demonstrate in live cells from normal individuals because individual variations in DNA repair capacities (DRC) are too low to be measured easily. Such lack of information has been hindering progress in developing personalized disease prevention and intervention protocols, especially among exposed populations. However, using a variety of challenge assays as biomarkers, variations in individual's DRC can be amplified in live cells and be determined. Furthermore, evidence indicates that DRC are not only inherited but can also be modified by environmental factors (e.g., nutritional status and exposure to genotoxic substances). Using these challenge assays, e.g., in live lymphocytes, individual's DRC can be holistically and functionally determined as well as quantitated. With the more precise information, assessment of health risk can be better determined on an individual rather than on a population basis. This review provides a succinct summary on the development and application of recent challenge assays in lymphocytes which can provide measurements of individuals' DRC, and on the latest data for more precise disease prevention and intervention.

Norfloxacin adsorption and subsequent degradation on ball-milling tailored N-doped biochar.

N-doping is an effective way to modify biochar for enhancing the adsorption capacity. The synthesis of N-doped biochar by the ball-milling method has been attractive due to its facile and eco-friendly approach with low energy consumption. However, the commonly used N-precursor NH3·H2O is environmentally harmful. It is needed to prepare safe and non-toxic N-doped biochar for large-scale production. Here, a urea N-doped biochar (U-MBC) was prepared by the ball-milling method and used for norfloxacin (NOR) removal. The results showed that U-MBC exhibited almost 4-fold higher adsorption capacity for NOR than pristine biochar in a wide pH range (3-9). The adsorption enhancement was owing to the enhancement of H-bonds, π-π electron donor-acceptor, and pore-filling interactions due to the N-doping and ball-milling method. Additionally, 89% of adsorbed NOR can be further removed after 6 h milling. The regenerated U-MBC still had a good adsorption capacity (46.27 mg g-1) and performed well in three cycles. The knowledge gained from this study could encourage researchers to use urea or similar safe N-precursors with the ball-milling method for the large-scale production of N-doped biochar to remove antibiotic organic pollutants in the environment.

Carbon Yarn-Ball-Entangled SiO2 Anode with Excellent Electrochemical Performance for Lithium-Ion Batteries.

Various nanoscale SiO2 and their composites have demonstrated superior electrochemical performance as anodes for lithium-ion batteries. However, both the battery production and real applications require the integration of nanoscale SiO2 into micrometer-sized secondary particles while preserving their excellent stability and conductivity, which remains a great challenge. In this work, a unique carbon yarn-ball structure is successfully synthesized that entangles nanoscale SiO2 together to build a micrometer-sized secondary particle. The hook-like carbon wires closely adhere to individual SiO2 nanoparticles, which constitute the basic unit of the yarn-ball structure. The entangled carbon wires create a network of electron conduction highways for SiO2 , and the yarn-ball structure provides a resilient 3D matrix that can effectively buffer the anisotropic volume changes of SiO2 during Li ion insertion/extraction. Under 0.1 A g-1 , the carbon yarn-ball-entangled SiO2 can deliver a 1297 mAh g-1 discharge capacity with a small irreversible capacity of 82 mAh g-1 . The entangled carbon yarn ball firmly maintains its structural integrity during high-rate cycling (1 A g-1 ), which gives rise to a large accessible capacity (709 mAh g-1 , 90.7% retention for 500 cycles), superior coulombic efficiency (>99.9%), and excellent structural stability.

Manganese-promoted cleavage of acetylacetonate resembling the ß-diketone cleaving dioxygenase (Dke1) reactivity.

We here report a manganese-based oxidative cleavage of inactivated acetylacetonate, the mechanistic pathway of which resembles Dke1-catalyzed reactions of ß-diketone and α-keto acid. This oxidative transformation proceeds through an acetylacetonate-pyruvate-oxalate pathway, which can be terminated at the stage of pyruvate through ligand/solvent variation. XRD, time-dependent GC-MS, and isotope-labeling studies suggested that our system represents the same cleaving specificity and dioxygenase-like reactivity of Dke1.

Changes in miR-222 expression, DNA repair capacity, and MDM2-p53 axis in association with low-dose benzene genotoxicity and hematotoxicity.

Mechanisms for hematotoxicity and health effects from exposure to low doses of benzene (BZ) remain to be identified. To address the information gap, our investigation was focused onto using appropriate populations and cell cultures to investigate novel BZ-induced effects such as disruption of DNA repair capacity (DRC). From our study, abnormal miRNAs were identified and validated using lymphocytes from 56 BZ-poisoned workers and 53 controls. In addition, 173 current BZ-exposed workers and 58 controls were investigated for key miRNA expression using RT-PCR and for cellular DRC using a challenge assay. Subsequently, the observed activities in lymphocytes were verified using human HL-60 (p53 null) and TK6 (p53 wild-type) cells via 1,4-benzoquinone (1,4-BQ) treatment and miR-222 interferences. The targeting of MDM2 by miR-222 was validated using a luciferase reporter. Our results indicate induction of genotoxicity in lymphocytes from workers with low exposure doses to BZ. In addition, miR-222 expression was up-regulated among both BZ-poisoned and BZ-exposed workers together with inverse association with DRC. Our in vitro validation studies using both cell lines indicate that 1,4-BQ exposure increased expression of miR-222 and Comet tail length but decreased DRC. Loss of miR-222 reduced DNA damage, but induced S-phase arrest and apoptosis. However, silencing of MDM2 failed to activate p53 in TK6 cells. In conclusion, our in vivo observations were confirmed by in vitro studies showing that BZ/1,4-BQ exposures caused genotoxicity and high expression of miR-222 which obstructed expression of the MDM2-p53 axis that led to failed activation of p53, abnormal DRC and serious biological consequences.

Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity.

BACKGROUND: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits. OBJECTIVES: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD). METHODS: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n = 1896), micronuclei (MN) frequencies (n = 934), and relative telomere length (rTL) (n = 757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL). RESULTS: Among all participants, BLLs show a right-skewed distribution (median, 185.40 µg/L; 25th - 75th percentile, 104.63-271.70 µg/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175 µg/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70 µg/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64 µg/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43 µg/L for female. CONCLUSIONS: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105 µg/L based on RBC and Hb, and even more strict level of 66 and 35 µg/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.

Dataset on the effect of Benzene exposure on genetic damage, hematotoxicity, telomere length and polymorphisms in metabolic and DNA repair genes.

In this paper, we present an occupational dataset to evaluate benzene exposure on the effective biomarkers of genetic damage, indicated as cytokinesis-block micronucleus (MN) frequency, hematotoxicity, indicated as white blood cells (WBC) counts, and molecular marker of telomere length (TL). And we further to eliminate the mechanism of benzene induced damage. Then evaluate the effects of sites polymorphism in environmental response genes, including 18 sites in metabolic and DNA repair genes, and the interaction between gene polymorphism and benzene exposure. This dataset is supplementary to the submitted research by [1] focused on the biomarkers TL, and a detailed description of the subjects sampling, biomarkers detection, data analysis and discussion are discussed in detail.

Aberrant lncRNA Profiles Are Associated With Chronic Benzene Poisoning and Acute Myelocytic Leukemia.

OBJECTIVE: This study investigates the mechanisms of benzene hematotoxicity. METHODS: We used microarray to detect expression profiles of long non-coding RNAs (lncRNAs) and mRNAs in peripheral lymphocytes from chronic benzene poisoning, acute myelocytic leukemia, and healthy controls. The lncRNAs and mRNAs were validated using real-time quantitative PCR (RT-qPCR). Cytokinesis-block micronucleus assay was used to analyze chromosomal aberration. RESULTS: We found 173 upregulated and 258 downregulated lncRNAs, and 695 upregulated and 804 downregulated mRNAs. The lncRNA CUST_40243 and mRNA PDGFC and CDKN1A associated with chronic benzene poisoning. Relevant inflammatory response, hematopoietic cell lineage, and cell cycle may be important pathways for the sifted lncRNAs and mRNAs. Furthermore, micronuclei frequency was significantly higher in off-post chronic benzene poisoning patients. CONCLUSIONS: Chromosomal aberration induced by benzene exposure is irreversible. The lncRNA CUST_40243 and mRNA PDGFC and CDKN1A are related to chronic benzene poisoning.

Interaction effects of environmental response gene polymorphisms and benzene exposure on telomere length in shoe-making workers.

Benzene is a globally occurring environmental and occupational pollutant that causes leukemia. To better understand telomere length (TL) as a function of benzene toxicity, we recruited 294 shoe-making workers and 102 controls from Wenzhou, China in 2011. Biomarkers of TL, cytokinesis-block micronucleus (MN) frequency, and white blood cells (WBC) were measured. In total, 18 polymorphic sites in environmental response genes, including metabolic and DNA repair genes, were analyzed. Results indicate that benzene exposure led to a longer TL at a threshold of 32 mg/m3-year of cumulative exposure dose (CED). Furthermore, the TL was longer in members of the damaged group, when evaluated for MN frequency (P < 0.001) and reduced WBC (P < 0.001), than in those of the normal group. Workers carrying genotype TT (ß = 0.32, P = 0.042) in rs3212986 of ERCC1 and genotype TC (ß = 0.24, P = 0.082) in rs1051740 of mEH exon3 were associated with a longer TL as compared to the wild-type group. TA (ß = -0.53, P < 0.001) in rs6413432 of CYP2E1 was associated with a shorter TL. Benzene exposure interacted with the TA type in rs6413432 (ß = 0.003, 95% CI: 0, 0.006, P = 0.042) and the CC type in rs1051740 (ß = 0.007, 95% CI: 0.001, 0.013, P = 0.015) after adjusting for confounding factors. Our results indicate that benzene induces an increase in TL at a threshold of CED ≥32mg/m3-year. Rs1051740, rs3212986, and rs6413432 were found to be involved in benzene-induced telomere growth; in particular, rs1051740 and rs6413432 interacted with the benzene exposure, resulting in an extended TL.

PIG-A gene mutation as a genotoxicity biomarker in human population studies: An investigation in lead-exposed workers.

The rodent Pig-a gene mutation assay has demonstrated remarkable sensitivity in identifying in vivo mutagens, while much less is known about the value of the human PIG-A assay for risk assessment. To obtain more evidence of its potential as a predictive biomarker for carcinogen exposure, we investigated PIG-A mutant frequencies (MFs), along with performing the Comet assay and micronucleus (MN) test, in 267 workers occupationally exposed to lead. Multivariate Poisson regression showed that total red blood cell PIG-A MFs were significantly higher in lead-exposed workers (10.90 ± 10.7 × 10-6 ) than in a general population that we studied previously (5.25 ± 3.6 × 10-6 ) (p < .0001). In contrast, there was no increase in lymphocyte MN frequency or in DNA damage as measured by percentage comet tail intensity in whole blood cells. Current year worker blood lead levels (BLL), an exposure biomarker, were elevated (232.6 ± 104.6 µg/L, median: 225.4 µg/L); a cumulative blood lead index (CBLI) also was calculated based on a combination of current and historical worker BLL data. Chi-square testing indicated that PIG-A MFs were significantly related to CBLI (p = .0249), but independent of current year BLL (p = .4276). However, % comet tail intensity and MN frequencies were better associated with current year BLL than CBLI. This study indicates that the PIG-A assay could serve as biomarker to detect the genotoxic effects of lead exposure and demonstrates that a battery of genotoxicity biomarkers having mechanistic complementarity may be useful for comprehensively monitoring human carcinogenic risk.