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Objective: Essential metals play important roles in the carcinogenic process. However, seldom longitudinal investigations have evaluated their roles in lung cancer development. We aimed to investigate the associations between multiple essential metals and lung cancer incidence and to explore the potential mechanisms., Methods: A nested case-control study of 440 incident lung cancer cases and 1:3 frequency matched 1320 healthy controls from the Dongfeng-Tongji Cohort was conducted. The baseline plasma concentrations of 11 essential metals (cobalt, copper, iron, manganese, molybdenum, rubidium, selenium, strontium, stannum, vanadium, and zinc) were measured, and their associations with lung cancer incidence were estimated. Effect of positive metal (zinc) on 4-year telomere attrition was then evaluated among an occupational cohort of 724 workers. We also assessed the transcriptional regulation effects of plasma zinc on mRNA expression profiles, and the expressions of zinc-related genes were further compared in pair-wised lung tumor and normal tissues., Results: Elevated plasma level of zinc was associated with lower incident risk of lung cancer [OR (95% CI) = 0.89 (0.79, 0.99)] and decreased 4-year telomere attrition [β (95% CI) = -0.73 (-1.27, -0.19)]. These effects were pronounced among males. In particularly, zinc could regulate the expressions of 8 cancer-related genes, including SOD1, APE, TP53BP1, WDR33, LAPTM4B, TRIT1, HUWE1, and ZNF813, which were over-expressed in lung tumor tissues., Conclusions: We propose that high plasma zinc could prevent incident lung cancer, probably by slowing down telomere attrition and regulating the expressions of cancer-related genes. These results provided a new insight into lung cancer prevention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aimed to investigate the associations of multiple metals with chromosome damage, and further explore the mediation roles of microRNAs (miRNAs) and their potentials in lung cancer., Methods: We determined the urinary levels of 23 metals, lymphocytic micronucleus (MN) frequency, and ten candidate miRNAs in plasma among 365 healthy workers. Poisson and linear regression models were conducted to analyze the associations of urinary metals with MN frequency and miRNAs, respectively. The mediation effects of miRNAs on the metal-MN frequency associations were assessed by causal mediation analysis. Additionally, the levels of effective metal and miRNAs were measured in 43 pair-wised tumor and normal lung tissues., Results: The urinary level of titanium was inversely associated with MN frequency after Bonferroni correction [frequency ratio (FR) and 95% confidence interval (95%CI) = 0.88 (0.82, 0.94), p = 5.0 × 10 -4 ]. A doubling in urinary titanium was associated with 14.72%-38.17% decrease in plasma miRNAs. After multiple comparison, miR-24-3p and miR-28-5p significantly mediated 24.8% (7.7%, 70.0%) and 20.4% (5.7%, 52.0%) of the association between titanium and MN frequency (p mediation  = 0.002 and 0.004, respectively). Besides, a doubling in titanium was associated with a separate 53.4% and 47.2% decreased miR-24-3p and miR-28-5p expression in normal lung tissues. Lower titanium but higher levels of miR-24-3p and miR-28-5p were shown in tumor than normal tissues of lung squamous cell carcinoma patients (all p < 0.05)., Conclusions: Our study proposed the negative associations of titanium with chromosome damage and lung cancer, and highlighted the mediating roles of miR-24-3p and miR-28-5p. Further investigations are warranted to validate these associations and uncover the underlying mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAHs) are well-acknowledged pro-inflammatory chemicals, but their associations with blood cell-based inflammatory biomarkers need further investigation. Moreover, the effects and mechanisms of essential metals on PAH-related inflammation remain poorly understood. To elucidate the associations of PAHs on inflammatory biomarkers, as well as the effects and mechanisms of essential metals on these associations. A cross-sectional study was conducted on 1388 coke oven workers. We analyzed the modification effects of key essential metal(s) on PAHs-inflammatory biomarkers associations. To explore the possible mechanisms from an inflammation perspective, we performed a bioinformatic analysis on the genes of PAHs and essential metals obtained from the Comparative Toxicogenomics Database (CTD) and performed a mediation analysis. We observed associations of PAHs and essential metals with lymphocyte-to-monocyte ratio (LMR) (P < 0.05). PAH mixtures were inversely associated with LMR (β QGC-index = −0.18, P < 0.001), with 1-hydroxypyrene (1-OH-Pyr) being the most prominent contributor (weight = 63.37 %), whereas a positive association between essential metal mixtures and LMR was observed (β QGC-index = 0.14, P < 0.001), with tin being the most significant contributor (weight = 51.61%). An inverse association of 1-OH-Pyr with LMR was weakened by increased tin exposure (P < 0.05). The CTD database showed that PAHs and tin compounds co-regulated 22 inflammation-associated genes, but they regulated most genes in opposite directions. Further identified the involvement of oxidative stress and mediation analysis showed that the mediation effect of 8-hydroxydeoxyguanosine (8-OHdG) on 1-OH-Pyr-LMR association presented heterogeneity between low and high tin tertile groups (I 2 = 37.84%). 1-OH-Pyr and tin were significantly associated with LMR. Modification effects indicated that the inverse association of 1-OH-Pyr with LMR was mitigated with an increase in tin. The mediation effect of 8-OHdG on the inverse association of 1-OH-Pyr with LMR may be partially dependent on tin. [Display omitted] • PAH mixtures were related to decreased LMR, with pyrene contributing the most. • Essential metals had joint effects on elevated LMR, with tin being predominant. • Tin had a modifying effect on pyrene-LMR association. • Pyrene and tin regulated inflammation-related common genes in opposite directions. • 8-OHdG mediated pyrene-LMR association and partially dependent on the dose of tin. [ABSTRACT FROM AUTHOR]

Whether adopting healthy lifestyles and maintaining moderate levels of essential metals could attenuate the reduction of heart rate variability (HRV) related to polycyclic aromatic hydrocarbons (PAHs) exposure are largely unknown. In this study, we measured urinary metals and PAHs as well as HRV, and constructed a healthy lifestyle score in 1267 coke oven workers. Linear regression models were used to explore the association of healthy lifestyle score and essential metals with HRV, and interaction analysis was performed to investigate the potential interaction between healthy lifestyle score, essential metals, and PAHs on HRV. Mean age of the participants was 41.9 years (84.5% male). Per one point higher healthy lifestyle score was associated with a 2.5% (95% CI, 1.0%–3.9%) higher standard deviation of all normal to normal intervals (SDNN), 2.1% (95% CI, 0.5%–3.6%) higher root mean square of successive differences in adjacent NN intervals (r-MSSD), 4.3% (95% CI, 0.4%–8.2%) higher low frequency, 4.4% (95% CI, 0.2%–8.5%) higher high frequency, and 4.4% (95% CI, 1.2%–7.6%) higher total power, respectively. Urinary level of chromium was positively associated with HRV indices, with the corresponding β (95% CI) (%) was 5.17 (2.84, 7.50) for SDNN, 4.29 (1.74, 6.84) for r-MSSD, 12.26 (6.08, 18.45) for low frequency, 12.61 (5.87, 19.36) for high frequency, and 11.31 (6.19, 16.43) for total power. Additionally, a significant interaction was found between healthy lifestyle score and urinary total hydroxynaphthalene on SDNN (P interaction = 0.04), and higher level of urinary chromium could attenuate the adverse effect of total hydroxynaphthalene level on HRV (all P interaction <0.05). Findings of our study suggest adopting healthy lifestyle and maintaining a relatively high level of chromium might attenuate the reduction of HRV related to total hydroxynaphthalene exposure. [ABSTRACT FROM AUTHOR]

Mosaic loss of chromosome Y (mLOY) is an indicator of genome instability, but the environmental stressors of mLOY remained largely unknown. In this study, we detected the internal exposure levels of 11 polycyclic aromatic hydrocarbon (PAH) metabolites and 22 metals among 888 coke-oven workers, and calculated their blood mLOY based on genome-wide SNP genotyping data and presented as median log R ratio (mLRR-Y). The generalized linear model (GLM), LASSO, and Bayesian kernel machine regression (BKMR), were used to select mLOY-relevant chemicals. The results of these models consistently suggested the negative dose-response relationships of urinary 1-hydroxynaphthalene (1-OHNa), antimony (Sb), and molybdenum (Mo) with mLRR-Y. There were no pairwise interactions between these three chemicals (P interaction > 0.05), but subjects with high exposure to ≥ 2 kinds of these chemicals showed reducing mLRR-Y [β(95%CI) = − 0.015(− 0.023, − 0.008)], increasing oxidative DNA damage (marked by 8-hydroxydeoxyguanosine) [β(95%CI) = 0.625(0.454, 0.796)] and chromosome damage (marked by micronucleus frequency in lymphocytes) [frequency ratio (FR) and 95%CI = 1.146(1.047, 1.225)] than those with low exposure to all these chemicals. The combined effects of 1-OHNa, Sb, and Mo on elevating DNA damage may partly explain their joint effects on increased blood mLOY. These results provided a new insight into environmental hazards co-exposure on chromosome-Y deletions. [Display omitted] • Effects of environmental chemical mixtures on mLOY remain largely unknown. • The GLM, LASSO, and BKMR were used to explore the environmental stressors of mLOY. • High exposure to 1-OHNa, Sb, and Mo were associated with elevated mLOY. • 1-OHNa, Sb, and Mo co-exposure take joint effects on mLOY, 8-OHdG, and MN frequency. [ABSTRACT FROM AUTHOR]

• Increased plasma manganese level is positively associated with telomere length. • Multipollutant associations suggest manganese as a sole predictor for telomere length. • Manganese has joint effects with TERT-CLPTM1L variants on increasing telomere length. • This study offered clues for the early prevention of telomere shortening related diseases. Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL). This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL. Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [β(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 μg/L) showed joint effects on increasing LTL. Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]