Urine is better for rare earth elements bimonitoring in long-term exposed population: An exposure-response relationship study.

With the soaring use of rare earth elements (REEs) worldwidely in high-technology and clean energy industries, there were growing concerns for adverse health effect from the REEs exposure. However, there is a lack of biomonitoring research concerning both urine and blood in population with definite exposure. We performed a biomonitoring study that involved 103 REEs exposed males and 110 males as non-REEs exposed controls. We measured the levels of REEs in environment and urine and blood samples from participants, and explored the exposure-response relationship between REEs in environment and body fluids. The effects of exposure duration and smoking status on the internal exposure level of REEs were also investigated. The results showed environmental REEs level of exposure group was significantly higher than that of control group (range of geometric mean of exposure vs. control: 1.08-4.07 × 104 ng/m3 vs.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.

The key metabolic signatures and biomarkers of polycyclic aromatic hydrocarbon-induced blood glucose elevation in chinese individuals exposed to diesel engine exhaust.

Due to the complexity of environmental exposure factors and the low levels of exposure in the general population, identifying the key environmental factors associated with diabetes and understanding their potential mechanisms present significant challenges. This study aimed to identify key polycyclic aromatic hydrocarbons (PAHs) contributing to increased fasting blood glucose (FBG) concentrations and to explore their potential metabolic mechanisms. We recruited a highly PAH-exposed diesel engine exhaust testing population and healthy controls. Our findings found a positive association between FBG concentrations and PAH metabolites, identifying 1-OHNa, 2-OHPh, and 9-OHPh as major contributors to the rise in FBG concentrations induced by PAH mixtures. Specifically, each 10 % increase in 1-OHNa, 2-OHPh, and 9-OHPh concentrations led to increases in FBG concentrations of 0.201 %, 0.261 %, and 0.268 %, respectively. Targeted metabolomics analysis revealed significant alterations in metabolic pathways among those exposed to high levels of PAHs, including sirtuin signaling, asparagine metabolism, and proline metabolism pathway. Toxic function analysis highlighted differential metabolites involved in various dysglycemia-related conditions, such as cardiac arrhythmia and renal damage. Mediation analysis revealed that 2-aminooctanoic acid mediated the FBG elevation induced by 2-OHPh, while 2-hydroxyphenylacetic acid and hypoxanthine acted as partial suppressors. Notably, 2-aminooctanoic acid was identified as a crucial intermediary metabolic biomarker, mediating significant portions of the associations between the multiple different structures of OH-PAHs and elevated FBG concentrations, accounting for 16.73 %, 10.84 %, 10.00 %, and 11.90 % of these effects for 1-OHPyr, 2-OHFlu, the sum concentrations of 2- and 9-OHPh, and the sum concentrations of total OH-PAHs, respectively. Overall, our study explored the potential metabolic mechanisms underlying the elevated FBG induced by PAHs and identified 2-aminooctanoic acid as a pivotal metabolic biomarker, presenting a potential target for intervention.

Particulate Matter and Its Components Induce Alteration on the T-Cell Response: A Population Biomarker Study.

Compared with the T-cell potential of particulate matter (PM) in animal studies, comprehensive evaluation on the impairments of T-cell response and exposure-response from PM and its components in human population is limited. There were 768 participants in this study. We measured environmental PM and its polycyclic aromatic hydrocarbons (PAHs) and metals and urinary metabolite levels of PAHs and metals among population. T lymphocyte and its subpopulation (CD4+ T cells and CD8+ T cells) and the expressions of T-bet, GATA3, RORγt, and FoxP3 were measured. We explored the exposure-response of PM compositions by principal component analysis and mode of action by mediation analysis. There was a significant decreasing trend for T lymphocytes and the levels of T-bet and GATA3 with increased PM levels. Generally, there was a negative correlation between PM, urinary 1-hydroxypyrene, urinary metals, and the levels of T-bet and GATA3 expression. Additionally, CD4+ T lymphocytes were found to mediate the associations of PM2.5 with T-bet expression. PM and its bound PAHs and metals could induce immune impairments by altering the T lymphocytes and genes of T-bet and GATA3.

Alterations to biomarkers related to long-term exposure to diesel exhaust at concentrations below occupational exposure limits in the European Union and the USA.

BACKGROUND: We previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear. METHODS: In a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (<106 µg/m3), below the European Union (EU) OEL (<50 µg/m3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (<20 µg/m3). RESULTS: Below the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1ß (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19). CONCLUSIONS: DEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

Pre- and postnatal particulate matter exposure and blood pressure in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Early life is a susceptible period of air pollution-related adverse health effects. Hypertension in children might be life-threatening without prevention or treatment. Nevertheless, the causative association between environmental factors and childhood hypertension was limited. In the light of particulate matter (PM) as an environmental risk factor for cardiovascular diseases, this study investigated the association of pre- and postnatal PM exposure with blood pressure (BP) and hypertension among children and adolescents. METHOD: Four electronic databases were searched for related epidemiological studies published up to September 13, 2022. Stata 14.0 was applied to examine the heterogeneity among the studies and evaluate the combined effect sizes per 10 µg/m3 increase of PM by selecting the corresponding models. Besides, subgroup analysis, sensitivity analysis, and publication bias test were also conducted. RESULTS: Prenatal PM2.5 exposure was correlated with increased diastolic blood pressure (DBP) in offspring [1.14 mmHg (95% CI: 0.12, 2.17)]. For short-term postnatal exposure effects, PM2.5 (7-day average) was significantly associated with systolic blood pressure (SBP) [0.20 mmHg (95% CI: 0.16, 0.23)] and DBP [0.49 mmHg (95% CI: 0.45, 0.53)]; and also, PM10 (7-day average) was significantly associated with SBP [0.14 mmHg (95% CI: 0.12, 0.16)]. For long-term postnatal exposure effects, positive associations were manifested in SBP with PM2.5 [ß = 0.44, 95% CI: 0.40, 0.48] and PM10 [ß = 0.35, 95% CI: 0.19, 0.51]; DBP with PM1 [ß = 0.45, 95% CI: 0.42, 0.49], PM2.5 [ß = 0.31, 95% CI: 0.27, 0.35] and PM10 [ß = 0.32, 95% CI: 0.19, 0.45]; and hypertension with PM1 [OR = 1.43, 95% CI: 1.40, 1.46], PM2.5 [OR = 1.65, 95% CI: 1.29, 2.11] and PM10 [OR = 1.26, 95% CI: 1.09, 1.45]. CONCLUSION: Both prenatal and postnatal exposure to PM can increase BP, contributing to a higher prevalence of hypertension in children and adolescents.

Short-term exposure to antimony induces hepatotoxicity and metabolic remodeling in rats.

Antimony (Sb) poses a significant threat to human health due to sharp increases in its exploitation and application globally, but few studies have explored the pathophysiological mechanisms of acute hepatotoxicity induced by Sb exposure. We established an in vivo model to comprehensively explore the endogenous mechanisms underlying liver injury induced by short-term Sb exposure. Adult female and male Sprague-Dawley rats were orally administrated various concentrations of potassium antimony tartrate for 28 days. After exposure, the serum Sb concentration, liver-to-body weight ratio, and serum glucose levels significantly increased in a dose-dependent manner. Body weight gain and serum concentrations of biomarkers of hepatic injury (e.g., total cholesterol, total protein, alkaline phosphatase, and the aspartate aminotransferase/alanine aminotransferase ratio) decreased with increasing Sb exposure. Through integrative non-targeted metabolome and lipidome analyses, alanine, aspartate, and glutamate metabolism; phosphatidylcholines; sphingomyelins; and phosphatidylinositols were the most significantly affected pathways in female and male rats exposed to Sb. Additionally, correlation analysis showed that the concentrations of certain metabolites and lipids (e.g., deoxycholic acid, N-methylproline, palmitoylcarnitine, glycerophospholipids, sphingomyelins, and glycerol) were significantly associated with hepatic injury biomarkers, indicating that metabolic remodeling may be involved in apical hepatotoxicity. Our study demonstrated that short-term exposure to Sb induces hepatotoxicity, possibly through a glycolipid metabolism disorder, providing an important reference for the health risks of Sb pollution.

Association between diesel exhaust exposure and mitochondrial DNA methylation.

OBJECTIVES: Diesel exhaust is an established human carcinogen, however the mechanisms by which it leads to cancer development are not fully understood. Mitochondrial dysfunction is an established contributor to carcinogenesis. Recent studies have improved our understanding of the role played by epigenetic modifications in the mitochondrial genome on tumorigenesis. In this study, we aim to evaluate the association between diesel engine exhaust (DEE) exposure with mitochondrial DNA (mtDNA) methylation levels in workers exposed to DEE. METHODS: The study population consisted of 53 male workers employed at a diesel engine manufacturing facility in Northern China who were routinely exposed to diesel exhaust in their occupational setting, as well as 55 unexposed male control workers from other unrelated factories in the same geographic area. Exposure to DEE, elemental carbon, organic carbon, and particulate matter (PM2.5) were assessed. mtDNA methylation for CpG sites (CpGs) from seven mitochondrial genes (D-Loop, MT-RNR1, MT-CO2, MT-CO3, MT-ATP6, MT-ATP8, MT-ND5) was measured in blood samples. Linear regression models were used to estimate the associations between DEE, elemental carbon, organic carbon and PM2.5 exposures with mtDNA methylation levels, adjusting for potential confounders. RESULTS: DEE exposure was associated with decreased MT-ATP6 (difference = -35.6%, P-value = 0.019) and MT-ATP8 methylation (difference = -30%, P-value = 0.029) compared to unexposed controls. Exposures to elemental carbon, organic carbon, and PM2.5 were also significantly and inversely associated with methylation in MT-ATP6 and MT-ATP8 genes (all P-values < 0.05). CONCLUSIONS: Our findings suggest that DEE exposure perturbs mtDNA methylation, which may be of importance for tumorigenesis.

Aberrant mitochondrial DNA methylation and declined pulmonary function in a population with polycyclic aromatic hydrocarbon composition in particulate matter.

Air pollution exposure has been found to be associated with epigenetic modification of the mitochondrial genome, which could subsequently induce adverse health outcomes. However, very limited studies exist regarding the association between fine particulate matter (PM2.5) exposure and pulmonary function at the molecular level of mitochondrial epigenetic changes. This study aimed to investigate the association of platelet mitochondrial DNA (mtDNA) methylation with occupational PM2.5 exposure and pulmonary function. First, 768 participants were occupationally exposed to polycyclic aromatic hydrocarbon (PAH)-enriched PM2.5 in a coke-oven plant in East China. The levels of PM2.5, PAH components bound to PM2.5, and urinary PAH metabolites in the workplace environment were measured as an internal dose, respectively. mtDNA methylation was measured by bisulfite pyrosequencing of two genes of ATP synthase (MT-ATP6 and MT-ATP8). Mediation analysis was conducted to evaluate the role of mtDNA methylation in pulmonary alteration induced by PAH. A decreasing trend of platelet mtDNA methylation was observed with increase in PM2.5 exposure across all participants. As an important PAH metabolite in urine, 1-hydroxypyrene (1-OHP) was significantly negatively associated with FEV1/FVC (Forced Expiratory Volume in 1s/Forced Vital Capacity) ratio. The participants with high serum folate levels (≥10 nmol/L) showed positive association between MT-ATP6 methylation and FEV1/FVC ratio. Mediation analysis suggested that MT-ATP6 methylation mediated the significant association of urinary 1-OHP with FEV1/FVC. Our findings suggested the methylation of platelet mitochondrial gene MT-ATP6 and FEV1/FVC to be negatively associated with PM exposure. Platelet mtDNA methylation acted as an intermediary between PAH exposure and lung function decline. The mitochondrial epigenetic regulation in platelets, in response to PM exposure, might be involved in subsequent progress of abnormal pulmonary function.

Elevated Alu retroelement copy number among workers exposed to diesel engine exhaust.

BACKGROUND: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number. METHODS: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m3) and Alu/Alb ratio. RESULTS: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01). CONCLUSION: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.

Polycyclic aromatic hydrocarbons in particulate matter and serum club cell secretory protein change among schoolchildren: A molecular epidemiology study.

Airborne particulate matter (PM) is a complex mixture containing various kinds of harmful components. Exposure to air PM is associated with childhood respiratory disease, but epidemiological data are limited concerning the circulating respiratory injury protein on the etiology of childhood respiratory disease. Specifically, the role of PM toxic components or its biological effective dose (adduct) in respiratory injury remains unclear. To demonstrate the dose-response relationship and the main mechanism on circulating club cell secretory protein (CC16) from PM compositions among children, we enrolled 273 boarding schoolchildren in China, including 110 and 163 children of whom were in the low- and high-PM exposed areas, respectively. In this study, we measured the internal exposure levels, including serum polycyclic aromatic hydrocarbons (PAH) adduct, urinary metals, and AhR expression, and detected the serum CC16 level as a lung injury marker. Environmental tobacco exposure in children was assessed by urinary cotinine. We found that significantly higher levels of serum CC16, benzo[a]pyridin-7,8-dihydroglycol-9,10-epoxide (BPDE)-albumin adduct, urinary molybdenum, selenium, arsenic, cadmium and barium, and lower level of AhR expression in high-PM exposed group. There was a good association between serum BPDE-albumin adduct and CC16 (ß = 0.222, P = 0.006). There was no association on urinary metals and serum CC16. BPDE-albumin adduct was directly associated with serum CC16 alternation [direct effect = 0.2044, 95% confidence interval (CI) = (0.0426, 0.36)]. PM could cause serum CC16 increased in children. PAH and its adduct might play a key role in lung injury during PM exposure.

Utility evaluation of HLA-B*13:01 screening in preventing trichloroethylene-induced hypersensitivity syndrome in a prospective cohort study.

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.

Association between ambient air pollution and pregnancy complications: A systematic review and meta-analysis of cohort studies.

BACKGROUND: Pregnancy complications, such as gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP), have a great impact on public health. Exposure to ambient air pollution during pregnancy may cause pregnancy complications. The aim of our study is to explore the risk of trimester-specific maternal exposure to air pollutants on complications of pregnancy. METHODS: PubMed, EMBASE, Web of Science, and Cochrane were systematically searched for cohort studies published before October 27, 2019 which reported the association between ambient air pollutants (PM2.5, PM10, CO, NO, NO2, NOx, O3, and SO2) and pregnancy complications (GDM, HDP, preeclampsia, and gestational hypertension) during different exposure windows. A meta-analysis was applied to combine relative risks (RRs) and their confidence intervals (CIs) from eligible studies. Quality assessment was conducted and Egger test was used to evaluate the publication bias. All statistical analyses were performed by STATA software (Version 15, StataCorp, College Station, Texas, USA). RESULTS: This meta-analysis consisted of 33 cohort studies conducted on 22,253,277 pregnant women. Meta-analyses showed during the first trimester, there were significant associations of PM10 with gestational hypertension (RR = 1.07, 95% CI: 1.02-1.12 per 10 µg/m3, I2 = 0.0%), of SO2 with GDM (RR = 1.04, 95% CI: 1.00-1.08 per 1 ppb increment, I2 = 54.1%), of PM2.5 with preeclampsia (RR = 0.97, 95% CI: 0.95-1.00 per 5 µg/m3, I2 = 4.1%). During the entire pregnancy, PM2.5 significantly increased the risk of hypertensive disorders of pregnancy (RR = 1.18, 95% CI: 1.02-1.34 per 5 µg/m3, I2 = 85.1%). Egger test indicated that wide-scale publication bias was unlikely. CONCLUSION: Maternal exposure to ambient air pollutants is associated with pregnancy complications especially during the first trimester. Further large multicenter cohort studies considering different constituents of pollutants, levels of disease severity, sensitive populations, and various exposure windows are warranted in the future research.

Carbon content in airway macrophages and genomic instability in Chinese carbon black packers.

Carbon black (CB) particulates as virtually pure elemental carbon can deposit deep in the lungs of humans. International Agency for Research on Cancer classified CB as a Group 2B carcinogen due to inconclusive human evidence. A molecular epidemiological study was conducted in an established cohort of CB packers (CBP) to assess associations between CB exposure and genomic instability in peripheral lymphocytes using cytokinesis-block micronucleus assay (CBMN). Carbon content in airway macrophages (CCAM) was quantified as a bio-effective dosimeter for chronic CB exposure. Dose-response observed in CBPs was compared to that seen in workers exposed to diesel exhaust. The association between CB exposure status and CBMN endpoints was identified in 85 CBPs and 106 non-CBPs from a 2012 visit and replicated in 127 CBPs and 105 non-CBPs from a 2018 visit. The proportion of cytoplasm area occupied by carbon particles in airway macrophages was over fivefold higher in current CBPs compared to non-CBPs and was associated with CBMN endpoints in a dose-dependent manner. CB aerosol and diesel exhaust shared the same potency of inducing genomic instability in workers. Circulatory pro-inflammatory factors especially TNF-α was found to mediate associations between CB exposure and CBMN endpoints. In vitro functional validation supported the role of TNF-α in inducing genomic instability. An estimated range of lower limits of benchmark dose of 4.19-7.28% of CCAM was recommended for risk assessment. Chronic CB exposure increased genomic instability in human circulation and this provided novel evidence supporting its reclassification as a human carcinogen.

Time-course effects of antioxidants and phase II enzymes on diesel exhaust particles-induced oxidative damage in the mouse lung.

Mechanisms responsible for diesel exhaust particle (DEP)-induced toxicity in respiratory disorders are poorly understood, recent experimental and controlled exposure studies suggested that oxidative stress might be involved. To investigate the time-course effects DEP on nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, mice were intratracheal instilled with 100 µg DEP/mouse and sacrificed after 30 min, 6 h, 12 h, 24 h, 48 h, and 72 h. We measured reactive oxygen species (ROS) as well as Nrf2 and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and phase II enzymes including heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM) in the lungs. Additionally, histopathological changes were examined. At 6 h, ROS peaked, most of the enzymes were activated, and the histology showed the lungs were damaged. At 12 h, ROS returned to normal level and CAT activity decreased, while protein expression of Nrf2, HO-1, NQO1, GCLC, and GCLM increased, and the lungs were recovering from damage. After 24 h, ROS started to decrease and Nrf2 showed a decreasing trend at both gene and protein levels, while the lung damage had been entirely restored. These results suggested that a single exposure to DEP induce transient oxidative stress in the lungs, with time-dependent effects on Nrf2 and antioxidant enzymes and phase II enzymes.

Polycyclic aromatic hydrocarbons exposure and hematotoxicity in occupational population: A two-year follow-up study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational pollutants. To date, the effect and mechanism by which PAHs exposure impaired hematopoietic system remains unclear. METHODS: We examined the capability of PAHs to disrupt hematopoiesis in a study of 639 male participants in China by measuring complete blood counts (CBC) in 2013 and 2014. Gas chromatography-mass spectrometry (GC/MS) method was used to measure airborne levels of PAHs and benzene. We measured 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (SPMA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urinary by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method. RESULTS: We found decreased dose-response of white blood cells, eosinophils, monocytes and lymphocytes with increased PAHs exposure in two consecutive years. We did not find association between benzene with CBC in our study. After stratification analysis by smoking status, the findings were highly consistent. White blood cells, monocytes and red blood cell counts were decreased in high urinary 8-OHdG group. CONCLUSIONS: Our study showed that PAHs could impair the hematopoietic system independently, and oxidative stress might play an important role in potential hematotoxicity.

Declining Pulmonary Function in Populations with Long-term Exposure to Polycyclic Aromatic Hydrocarbons-Enriched PM2.5.

This study assesses the effects of long-term exposure to ambient air pollutants on inflammatory response and lung function. We selected 390 male coke oven workers with exposure to polycyclic aromatic hydrocarbons (PAHs) and fine particulate matter (PM2.5) and 115 control workers. The average duration in the exposed group was 9.10 years. The total amount of PAHs was more enriched in PM2.5 which collected from the coke oven workshops compared with the control areas. Correspondingly, the internal PAHs exposure indicated by urinary 1-hydroxypyrene (1-OHP) in the exposure group increased 25.7-fold compared to that of the control group. Moreover, the increasing level of urinary 1-OHP was associated with the decrease of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC). In non-current smokers of exposure group, inverse correlation of 1-OHP with FEV1/FVC was also found. Particularly, an exposure duration-dependent decline in FEV1/FVC and mean forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%) indicated that small airways were functionally obstructed. Furthermore, the increasing serum high-sensitivity C-reactive protein (hs-CRP) was correlated with the decline in pulmonary function in all subjects. These findings provide a clue that long-term exposure to PAHs-enriched PM2.5 impairs pulmonary function in occupational population.

Occupational exposure to diesel engine exhaust and alterations in immune/inflammatory markers: a cross-sectional molecular epidemiology study in China.

The relationship between diesel engine exhaust (DEE), a known lung carcinogen, and immune/inflammatory markers that have been prospectively associated with lung cancer risk is not well understood. To provide insight into these associations, we conducted a cross-sectional molecular epidemiology study of 54 males highly occupationally exposed to DEE and 55 unexposed male controls from representative workplaces in China. We measured plasma levels of 64 immune/inflammatory markers in all subjects using Luminex bead-based assays, and compared our findings to those from a nested case-control study of these markers and lung cancer risk, which had been conducted among never-smoking women in Shanghai using the same multiplex panels. Levels of nine markers that were associated with lung cancer risk in the Shanghai study were altered in DEE-exposed workers in the same direction as the lung cancer associations. Among these, associations with the levels of CRP (ß= -0.53; P = 0.01) and CCL15/MIP-1D (ß = 0.20; P = 0.02) were observed in workers exposed to DEE and with increasing elemental carbon exposure levels (Ptrends <0.05) in multivariable linear regression models. Levels of a third marker positively associated with an increased lung cancer risk, CCL2/MCP-1, were higher among DEE-exposed workers compared with controls in never and former smokers, but not in current smokers (Pinteraction = 0.01). The immunological differences in these markers in DEE-exposed workers are consistent with associations observed for lung cancer risk in a prospective study of Chinese women and may provide some insight into the mechanistic processes by which DEE causes lung cancer.

Long-term exposure to diesel engine exhaust induces primary DNA damage: a population-based study.

OBJECTIVES: Diesel engine exhaust (DEE) is a ubiquitous environmental pollutant and is carcinogenic to humans. To seek early and sensitive biomarkers for prediction of adverse health effects, we analysed the components of DEE particles, and examined the genetic and oxidative damages in DEE-exposed workers. METHODS: 101 male diesel engine testing workers who were constantly exposed to DEE and 106 matched controls were enrolled in the present study. The components of DEE were analysed, including fine particulate matter (PM2.5), element carbon (EC), nitrogen dioxide (NO2), sulfur dioxide (SO2) and polycyclic aromatic hydrocarbons (PAHs). Postshift urine samples were collected and analysed for 1-hydroxypyrene (1-OHP), an internal exposure marker for DEE. Levels of DNA strand breaks and oxidised purines, defined as formamidopyrimidine-DNA glycosylase (FPG) sites in leucocytes, were measured by medium throughput Comet assay. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also used to determine the level of oxidative stress. RESULTS: We found higher levels of PM2.5, EC, NO2, SO2 and PAHs in the diesel engine testing workshop and significantly higher urinary 1-OHP concentrations in exposed subjects (p<0.001). Compared with controls, the levels of parameters in normal Comet and FPG-Comet assay were all significantly higher in DEE-exposed workers (p<0.001), and in a dose-dependent and time-dependent manner. There were no significant differences between DEE-exposed workers and controls in regard to leucocyte FPG sensitive sites and urinary 8-OHdG levels. CONCLUSIONS: These findings suggest that DEE exposure mainly induces DNA damage, which might be used as an early biomarker for risk assessment of DEE exposure.

Associations between DNA methylation in DNA damage response-related genes and cytokinesis-block micronucleus cytome index in diesel engine exhaust-exposed workers.

Recently, diesel engine exhaust (DEE) was reclassified as a known carcinogen to humans. DNA methylation alterations in DNA damage response (DDR)-related genes have the potential to affect DEE exposure-related cancer risk. However, the evidence regarding the association between DEE exposure and methylation alterations in DDR-related genes is limited. In 117 DEE-exposed workers and 112 non-DEE-exposed workers, we measured urinary concentrations of six mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs). We also determined the methylation levels of three DDR-related genes (p16, RASSF1A, and MGMT) and LINE-1 by bisulfite-pyrosequencing assay. We found that DEE-exposed workers exhibited significantly lower mean promoter methylation levels of p16, RASSF1A, and MGMT than non-DEE-exposed workers (all p < 0.001). In all study subjects and non-smoking workers, increasing quartiles of urinary summed OH-PAHs was associated with hypomethylation of p16, RASSF1A, and MGMT (all p < 0.05). In non-smoking workers, methylation in p16, RASSF1A, and MGMT decreased by 0.36 % [95 % confidential interval (CI): -0.60, -0.11 %], 0.46 % (95 % CI: -0.79, -0.14 %), and 0.55 % (95 % CI: -0.95, -0.15 %), respectively, in association with highest versus lowest quartile of urinary summed OH-PAHs. In addition, p16, RASSF1A, MGMT, and LINE-1 methylation levels showed negative correlations with cytokinesis-block micronucleus cytome index which was previously measured in the same workers (all p < 0.05). In conclusion, our results clearly indicated that DEE exposure and increased genetic damage were associated with hypomethylation of p16, RASSF1A, and MGMT. Future studies with larger sample size are needed to confirm these associations.