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Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel‐induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross‐sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two‐stage study, first measuring 405 miRNAs in a pilot study of six DEE‐exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1–79.7 μg/m3) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR‐191‐5p, miR‐93‐5p, miR‐423‐3p, miR‐122‐5p) and one miRNA was significantly higher (miR‐92a‐3p) in DEE exposed workers compared to controls. Of these miRNAs, miR‐191‐5p (ptrend =.001, FDR = 0.04) and miR‐93‐5p (ptrend =.009, FDR = 0.18) showed evidence of an inverse exposure–response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • High levels of PAH exposure were associated with elevated FBG, and three key OH-PAHs (1-OHNa, 2-OHPh, and 9-OHPh) were identified. • The sirtuin signaling, asparagine metabolism, and proline metabolism pathways were related to PAHs induced dysglycemia. • 2-Aminooctanoic acid as a novel biomarker mediated the association between different structural OH-PAHs and elevated FBG concentrations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen. Using a targeted proteomics approach, we aimed to identify proteins associated with DEE and characterize these markers to understand the mechanisms of DEE‐induced carcinogenicity. In this cross‐sectional molecular epidemiology study, we measured elemental carbon (EC) using a personal air monitor and quantified 1317 targeted proteins in the serum using the SOMAScan assay (SOMALogic) among 19 diesel exposed factory workers and 19 unexposed controls. We used linear regressions to identify proteins associated with DEE and examined their exposure‐response relationship across levels of EC using linear trend tests. We further examined pathway enrichment of DEE‐related proteins using MetaCore. Occupational exposure to DEE was associated with altered levels of 22 serum proteins (permutation p <.01). Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed an exposure‐response relationship with EC (p trend <.01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, C‐X‐C Motif Chemokine Ligand 11 (CXCL11) showed the most significant association with DEE (β = −0.25; permutation p =.00004), where mean serum levels were 4121.1, 2356.7, and 2298.8 relative fluorescent units among the unexposed, lower exposed (median, range : 56.9, 40.2–62.1 μg/m3 EC), and higher exposed (median, range of EC: 72.9, 66.9–107.7 μg/m3 EC) groups, respectively (p trend =.0005). Pathway analysis suggested that these proteins are enriched in pathways related to inflammation and immune regulation. Our study suggests that DEE exposure is associated with altered serum proteins, which play a role in inflammation and immune regulation. [ABSTRACT FROM AUTHOR]

Urinary mutagenicity reflects systemic exposure to complex mixtures of genotoxic/carcinogenic agents and is linked to tumor development. Coal combustion emissions (CCE) and diesel engine exhaust (DEE) are associated with cancers of the lung and other sites, but their influence on urinary mutagenicity is unclear. We investigated associations between exposure to CCE or DEE and urinary mutagenicity. In two separate cross‐sectional studies of nonsmokers, organic extracts of urine were evaluated for mutagenicity levels using strain YG1041 in the Salmonella (Ames) mutagenicity assay. First, we compared levels among 10 female bituminous (smoky) coal users from Laibin, Xuanwei, China, and 10 female anthracite (smokeless) coal users. We estimated exposure–response relationships using indoor air concentrations of two carcinogens in CCE relevant to lung cancer, 5‐methylchrysene (5MC), and benzo[a]pyrene (B[a]P). Second, we compared levels among 20 highly exposed male diesel factory workers and 15 unexposed male controls; we evaluated exposure‐response relationships using elemental carbon (EC) as a DEE‐surrogate. Age‐adjusted linear regression was used to estimate associations. Laibin smoky coal users had significantly higher average urinary mutagenicity levels compared to smokeless coal users (28.4 ± 14.0 SD vs. 0.9 ± 2.8 SD rev/ml‐eq, p = 2 × 10−5) and a significant exposure‐response relationship with 5MC (p = 7 × 10−4). DEE‐exposed workers had significantly higher urinary mutagenicity levels compared to unexposed controls (13.0 ± 10.1 SD vs. 5.6 ± 4.4 SD rev/ml‐eq, p =.02) and a significant exposure‐response relationship with EC (p‐trend = 2 × 10−3). Exposure to CCE and DEE is associated with urinary mutagenicity, suggesting systemic exposure to mutagens, potentially contributing to cancer risk and development at various sites. [ABSTRACT FROM AUTHOR]

The International Agency for Research on Cancer has classified diesel engine exhaust (DEE) as a human lung carcinogen. Given that inflammation is suspected to be an important underlying mechanism of lung carcinogenesis, we evaluated the relationship between DEE exposure and the inflammatory response using data from a cross‐sectional molecular epidemiology study of 41 diesel engine testing workers and 46 unexposed controls. Repeated personal exposure measurements of PM2.5 and other DEE constituents were taken for the diesel engine testing workers before blood collection. Serum levels of six inflammatory biomarkers including interleukin (IL)‐1, IL‐6, IL‐8, tumor necrosis factor (TNF)‐α, macrophage inflammatory protein (MIP)‐1β, and monocyte chemotactic protein (MCP)‐1 were analyzed in all subjects. Compared to unexposed controls, concentrations of MIP‐1β were significantly reduced by ∼37% in DEE exposed workers (P < 0.001) and showed a strong decreasing trend with increasing PM2.5 concentrations in all subjects (Ptrend < 0.001) as well as in exposed subjects only (Ptrend = 0.001). Levels of IL‐8 and MIP‐1β were significantly lower in workers in the highest exposure tertile of PM2.5 (>397 µg/m3) compared to unexposed controls. Further, significant inverse exposure‐response relationships for IL‐8 and MCP‐1 were also found in relation to increasing PM2.5 levels among the DEE exposed workers. Given that IL‐8, MIP‐1β, and MCP‐1 are chemokines that play important roles in recruitment of immunocompetent cells for immune defense and tumor cell clearance, the observed lower levels of these markers with increasing PM2.5 exposure may provide insight into the mechanism by which DEE promotes lung cancer. Environ. Mol. Mutagen. 59:144–150, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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 (β= −0.53; P = 0.01) and CCL15/MIP-1D (β = 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diesel engine exhaust (DEE), a ubiquitous environmental pollutant, has been associated with adverse health effects. Revelation of cellular and molecular changes is critical for understanding environmental exposure-related diseases. Although the molecular-level effects of DEE exposure have been investigated, whether it is associated with aberrant changes at cellular level is largely unknown at the population level. In the present study, we measured urinary concentrations of 6 mono-hydroxylated PAHs (OH-PAHs) and cytotoxicity-related endpoints including apoptosis and necrosis frequencies, and nuclear division cytotoxicity index (NDCI) in peripheral blood lymphocytes (PBLs) of 79 DEE-exposed workers and 59 non-DEE-exposed workers. We found that DEE-exposed workers had significantly higher necrosis frequency and lower NDCI than did non-DEE-exposed workers (bothp < 0.001). In all study subjects and nonsmoking workers, urinary summed OH-PAHs was associated with increased necrosis frequency and reduced NDCI. In nonsmoking workers, an interquartile range increase in urinary summed OH-PAHs was associated with 105.03% increase in necrosis frequency and 8.70% decrease in NDCI. Taking advantage of the previous measure of micronucleus frequency, we observed that micronucleus frequency was positively correlated with apoptosis and necrosis frequencies (r = 0.277,p = 0.047 andr = 0.452,p = 0.001, respectively) and negatively correlated with NDCI (r = −0.477,p < 0.001). In conclusion, our results suggested that DEE exposure was associated with increased necrosis frequency and further with reduced NDCI in PBLs, providing evidence of DEE exposure-induced cytotoxicity in humans. [ABSTRACT FROM PUBLISHER]

Diesel engine exhaust (DEE) is a predominant contributor to urban air pollution. The International Agency for Research on Cancer classified DEE as a group I carcinogen. Inflammatory response is considered to be associated with various health outcomes including carcinogenesis. However, human data linking inflammation with long-term DEE exposure are still lacking. In this study, a total of 137 diesel engine testing workers with an average exposure of 8.2 years and 108 unexposed controls were enrolled. Peripheral blood samples were collected from all subjects, and the association of DEE exposure with inflammatory biomarkers was analyzed. Overall, DEE exposed workers had a significant increase in the C-reactive protein (CRP) and a significant decrease in cytokines including interleukin (IL)-1β, IL-6, IL-8, and macrophage inflammatory protein (MIP)-1β compared to controls after adjusting for age, BMI, smoking status, and alcohol use, and findings were highly consistent when stratified by smoking status. In addition, exposure time dependent patterns for IL-6 and CRP were also found (Ptrend = 0.006 and 0.026, respectively); however, the levels of IL-1β and MIP-1β were significantly lower in subjects with a DEE working time of less than 10 years compared with the controls and then recovered to control levels in workers exposed for >10 years. There were no significant differences in blood cell counts and major lymphocyte subsets between exposed workers and the controls. Our results provide epidemiological evidence for the relationship between DEE exposure and immunotoxicity considering the important roles of cytokines in immunological processes. [ABSTRACT FROM AUTHOR]

The International Agency for Research on Cancer has recently reclassified diesel engine exhaust (DEE) as a Group 1 carcinogen. Micronucleus (MN), nucleoplasmic bridge (NPB), and nuclear bud (NBUD) frequencies in peripheral blood lymphocytes (PBLs) are associated with cancer risk. However, the impact of DEE exposure on MN frequency has not been thoroughly elucidated due to mixed exposure and its impact on NPB and NBUD frequencies has never been explored in humans. We recruited 117 diesel engine testing workers with exclusive exposure to DEE and 112 non-DEE-exposed workers, and then we measured urinary levels of 4 mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) using high-performance liquid chromatography-mass spectrometry as well as MN, NPB, and NBUD frequencies in PBLs using cytokinesis-block MN assay. The DEE-exposed workers exhibited significantly higher MN, NPB, and NBUD frequencies than the non-DEE-exposed workers (P < 0.05). Among all study subjects, increasing levels of all 4 urinary OH-PAHs, on both quartile and continuous scales, were associated with increased MN, NPB, and NBUD frequencies (all P < 0.05). When the associations were analyzed separately in DEE-exposed and non-DEE-exposed workers, we found that the association between increasing quartiles of urinary 9-hydroxyphenanthrene (9-OHPh) and MN frequencies persisted in DEE-exposed workers (P = 0.001). The percent of MN frequencies increased, on average, by 23.99% (95% confidential interval, 9.64–39.93) per 1-unit increase in ln-transformed 9-OHPh. Our results clearly show that exposure to DEE can induce increases in MN, NPB, and NBUD frequencies in PBLs and suggest that DEE exposure level is associated with MN frequencies. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract Unlabelled Image Highlights • Single exposure to DEP induced a transient oxidative stress in lung. • Nrf2 were activated in response of oxidative stress caused by DEP. • Antioxidant enzymes and phase II enzymes revealed time course effects after DEP exposure. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • DEP exposure induced pulmonary neutrophils infiltration and IL-6 protein level increasing. • DEP exposure triggered increased LIN28B protein level and decreased levels of let-7d and let-7g. • By elevating LIN28B protein level, DEP exposure down-regulates the levels of let-7d and let-7g. • By decreasing the levels of let-7d and let-7g, DEP exposure up-regulates IL-6 level. Abstract Exposure to diesel exhaust particle (DEP) is closely related to inflammatory response in respiratory system. To understand the underlying molecular mechanism by which DEP induces pulmonary inflammatory response, we conducted DEP exposure experiments in vivo and in vitro. In vivo , each mouse was exposed to DEP suspension (100 μg of DEP) or vehicle only once in single intra-tracheal instillation (IT) section, or was exposed to DEP suspension (12.5 μg or 50 μg of DEP) or vehicle 12 times in repeated IT section. DEP exposure induced significant pathological injuries with substantial neutrophils infiltration and the increased level of pro-inflammatory cytokine IL-6 in mouse lungs. Consistently, elevated IL6 mRNA level was also observed in DEP treatment group (100 μg/ml) in vitro. In addition, DEP exposure exerted the similar influence on the expression of let-7d and let-7g microRNAs in vivo and in vitro. To verify the possible role of LIN28B/let-7 axis in the regulation of IL6 expression following DEP exposure, we applied RNAi technology in vitro , and found increased IL6 mRNA expression was alleviated or neutralized in DEP exposure groups after LIN28B silencing or after let-7d or let-7g over-expression. Taken together, we conclude that LIN28B/let-7 axis might be involved in inflammatory response induced by DEP exposure. [ABSTRACT FROM AUTHOR]

Diesel exhaust has long been of health concern due to established toxicity including carcinogenicity in humans. However, the precise components of diesel engine emissions that drive carcinogenesis are still unclear. Limited work has suggested that nitrated polycyclic aromatic hydrocarbons (NPAHs) such as 1-nitropyrene and 2-nitrofluorene may be more abundant in diesel exhaust. The present study aimed to examine whether urinary amino metabolites of these NPAHs were associated with high levels of diesel engine emissions and urinary mutagenicity in a group of highly exposed workers including both smokers and nonsmokers. Spot urine samples were collected immediately following a standard work shift from each of the 54 diesel engine testers and 55 non-tester controls for the analysis of five amino metabolites of NPAHs, and cotinine (a biomarker of tobacco smoke exposure) using liquid chromatography–mass spectrometry. An overnight urine sample was collected in a subgroup of non-smoking participants for mutagenicity analysis using strain YG1041 in the Salmonella (Ames) mutagenicity assay. Personal exposure to fine particles (PM 2.5) and more-diesel-specific constituents (elemental carbon and soot) was assessed for the engine testers by measuring breathing-zone concentrations repeatedly over several full work shifts. Results showed that it was 12.8 times more likely to detect 1-aminopyrene and 2.9 times more likely to detect 2-aminofluorene in the engine testers than in unexposed controls. Urinary concentrations of 1-aminopyrene were significantly higher in engine testers (p < 0.001), and strongly correlated with soot and elemental carbon exposure as well as mutagenicity tested in strain YG1041 with metabolic activation (p < 0.001). Smoking did not affect 1-aminopyrene concentrations and 1-aminopyrene relationships with diesel exposure. In contrast, both engine emissions and smoking affected 2-aminofluorene concentrations. The results confirm that urinary 1-aminopyrene may serve as an exposure biomarker for diesel engine emissions and associated mutagenicity. [ABSTRACT FROM AUTHOR]

Etheno-DNA adducts are biomarkers for assessing oxidative stress. In this study, the aim was to detect the level of etheno-DNA adducts and explore the relationship between the etheno-DNA adducts and genotoxicity biomarkers of the diesel engine exhaust (DEE)-exposed workers. We recruited 86 diesel engine testing workers with long-term exposure to DEE and 99 non-DEE-exposed workers. The urinary mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and etheno-DNA adducts (εdA and εdC) were detected by HPLC–MS/MS and UPLC–MS/MS, respectively. Genotoxicity biomarkers were also evaluated by comet assay and cytokinesis-block micronucleus assay. The results showed that urinary εdA was significantly higher in the DEE-exposed workers ( p < 0.001), exhibited 2.1-fold increase compared with the non-DEE-exposed workers. The levels of urinary OH-PAHs were positively correlated with the level of εdA among all the study subjects ( p < 0.001). Moreover, we found that the increasing level of εdA was significantly associated with the increased olive tail moment, percentage of tail DNA, or frequency of micronucleus in the study subjects ( p < 0.01). No significant association was observed between the εdC level and any measured genotoxicity biomarkers. In summary, εdA could serve as an indicator for DEE exposure in the human population. [ABSTRACT FROM AUTHOR]

We investigated whether exposure to carcinogenic diesel engine exhaust (DEE) was associated with altered adduct levels in human serum albumin (HSA) residues. Nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS) was used to measure adducts of Cys34 and Lys525 residues in plasma samples from 54 diesel engine factory workers and 55 unexposed controls. An untargeted adductomics and bioinformatics pipeline was used to find signatures of Cys34/Lys525 adductome modifications. To identify adducts that were altered between DEE-exposed and unexposed participants, we used an ensemble feature selection approach that ranks and combines findings from linear regression and penalized logistic regression, then aggregates the important findings with those determined by random forest. We detected 40 Cys34 and 9 Lys525 adducts. Among these findings, we found evidence that 6 Cys34 adducts were altered between DEE-exposed and unexposed participants (i.e., 841.75, 851.76, 856.10, 860.77, 870.43, and 913.45). These adducts were biologically related to antioxidant activity. • Cys34/Lys525 adducts reflect long-lasting effects of reactive oxygen/electrophilic species. • Investigated Cys34/Lys525 adductome alterations among diesel engine exhaust exposed workers. • Six Cys34 adducts were altered between exposed and unexposed participants. • Reactive oxygen/electrophilic species are involved in carcinogenicity of diesel exhaust. [ABSTRACT FROM AUTHOR]

Environmental insults can lead to alteration in DNA methylation of specific genes. To address the role of altered DNA methylation in prediction of polycyclic aromatic hydrocarbons (PAHs) exposure-induced genetic damage, we recruited two populations, including diesel engine exhausts (low-level) and coke oven emissions (high-level) exposed subjects. The positive correlation was observed between the internal exposure marker (1-hydroxypyrene) and the extents of DNA damage (P < 0.05). The methylation of representative genes, including TRIM36 , RASSF1a , and MGMT in peripheral blood lymphocytes was quantitatively examined by bisulfite-pyrosequencing assay. The DNA methylation of these three genes in response to PAHs exposure were changed in a CpG-site-specific manner. The identified hot CpG site-specific methylation of three genes exhibited higher predictive power for DNA damage than the respective single genes in both populations. Furthermore, the dose-response relationship analysis revealed a nonlinear U-shape curve of TRIM36 or RASSF1a methylation in combined population, which led to determination of the threshold of health risk. Furthermore, we established a prediction model for genetic damage based on the unidirectional-alteration MGMT methylation levels. In conclusion, this study provides new insight into the application of multiple epi-biomarkers for health risk assessment upon PAHs exposure. [Display omitted] [ABSTRACT FROM AUTHOR]