The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations.

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Mediation of association between benzo[a]pyrene exposure and lung cancer risk by plasma microRNAs: A Chinese case-control study.

Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the relationship is still unclear. Plasma microRNA (miRNA) is a typical epigenetic biomarker that was linked to environment exposure and lung cancer development. We aimed to reveal the mediation effect of plasma miRNAs on BaP-related lung cancer. We designed a lung cancer case-control study including 136 lung cancer patients and 136 controls, and measured the adducts of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) and sequenced miRNA profiles in plasma. The relationships between BPDE-Alb adducts, normalized miRNA levels and the risk of lung cancer were assessed by linear regression models. The mediation effects of miRNAs on BaP-related lung cancer were investigated. A total of 190 plasma miRNAs were significantly related to lung cancer status at Bonferroni adjusted P < 0.05, among which 57 miRNAs showed different levels with |fold change| > 2 between plasma samples before and after tumor resection surgery at Bonferroni adjusted P < 0.05. Especially, among the 57 lung cancer-associated miRNAs, BPDE-Alb adducts were significantly related to miR-17-3p, miR-20a-3p, miR-135a-5p, miR-374a-5p, miR-374b-5p, miR-423-5p and miR-664a-5p, which could in turn mediate a separate 42.2%, 33.0%, 57.5%, 36.4%, 48.8%, 32.5% and 38.2% of the relationship of BPDE-Alb adducts with the risk of lung cancer. Our results provide non-invasion biomarker candidates for lung cancer, and highlight miRNAs dysregulation as a potential intermediate mechanism by which BaP exposure lead to lung tumorigenesis.

Microscale Lateral Perovskite Light Emitting Diode Realized by Self-Doping Phenomenon.

High-definition near-eye display technology has extremely close sight distance, placing a higher demand on the size, performance, and array of light-emitting pixel devices. Based on the excellent photoelectric performance of metal halide perovskite materials, perovskite light-emitting diodes (PeLEDs) have high photoelectric conversion efficiency, adjustable emission spectra, and excellent charge transfer characteristics, demonstrating great prospects as next-generation light sources. Despite their potential, the solubility of perovskite in photoresist presents a hurdle for conventional micro/nano processing techniques, resulting in device sizes typically exceeding 50 µm. This limitation impedes the further downsizing of perovskite-based components. Herein, we propose a plane-structured PeLED device that can achieve microscale light-emitting diodes with a single pixel device size < 2 µm and a luminescence lifetime of approximately 3 s. This is accomplished by fabricating a patterned substrate and regulating ion distribution in the perovskite through self-doping effects to form a PN junction. This breakthrough overcomes the technical challenge of perovskite-photoresist incompatibility, which has hindered the development of perovskite materials in micro/nano optoelectronic devices. The strides made in this study open up promising avenues for the advancement of PeLEDs within the realm of micro/nano optoelectronic devices.

Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: A prospective case-cohort study.

Epidemiological investigations implied that mitochondrial DNA copy number (mtDNAcn) variations could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n = 278), gastric cancer (GC, n = 138), and esophageal cancer (EC, n = 72) as well as a random subcohort (n = 1173), who were followed up from baseline to the end of 2018. We determined baseline blood mtDNAcn and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Significant U-shaped associations were observed between mtDNAcn and GICs risks. Compared to subjects within the second quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3), and 4th (Q4) quartile subgroups showed increased risks of CRC (hazard ratio [HR] [95% confidence interval, CI] = 2.27 [1.47-3.52], 1.65 [1.04-2.62], and 2.81 [1.85-4.28], respectively) and total GICs (HR [95%CI] = 1.84 [1.30-2.60], 1.47 [1.03-2.10], and 2.51 [1.82-3.47], respectively], and those within Q4 subgroup presented elevated GC and EC risks (HR [95% CI] = 2.16 [1.31-3.54] and 2.38 [1.13-5.02], respectively). Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, smoking, and drinking status. This prospective case-cohort study showed U-shaped associations between mtDNAcn and GICs risks, but further research works are needed to uncover underlying biological mechanisms.

Multiple metals exposure and blood mitochondrial DNA copy number: A cross-sectional study from the Dongfeng-Tongji cohort.

OBJECTIVE: Mitochondria are essential organelles that execute fundamental biological processes, while mitochondrial DNA is vulnerable to environmental insults. The aim of this study was to investigate the individual and mixture effect of plasma metals on blood mitochondria DNA copy number (mtDNAcn). METHODS: This study involved 1399 randomly selected subcohort participants from the Dongfeng-Tongji cohort. The blood mtDNAcn and plasma levels of 23 metals were determined by using quantitative real-time polymerase chain reaction (qPCR) and inductively coupled plasma mass spectrometer (ICP-MS), respectively. The multiple linear regression was used to explore the association between each metal and mtDNAcn, and the LASSO penalized regression was performed to select the most significant metals. We also used the quantile g-computation analysis to assess the mixture effect of multiple metals. RESULTS: Based on multiple linear regression models, each 1% increase in plasma concentration of copper (Cu), rubidium (Rb), and titanium (Ti) was associated with a separate 0.16% [ß(95% CI) = 0.158 (0.066, 0.249), P = 0.001], 0.20% [ß(95% CI) = 0.196 (0.073, 0.318), P = 0.002], and 0.25% [ß(95% CI) = 0.245 (0.081, 0.409), P = 0.003] increase in blood mtDNAcn. The LASSO regression also confirmed Cu, Rb, and Ti as significant predictors for mtDNAcn. There was a significant mixture effect of multiple metals on increasing mtDNAcn among the elder participants (aged ≥65), with an approximately 11% increase in mtDNAcn for each quartile increase in all metal concentrations [ß(95% CI) = 0.146 (0.048, 0.243), P = 0.004]. CONCLUSIONS: Our results show that plasma Cu, Rb and Ti were associated with increased blood mtDNA, and we further revealed a significant mixture effect of all metals on mtDNAcn among elder population. These findings may provide a novel perspective on the effect of metals on mitochondrial dysfunction.

Frailty and its combined effects with lifestyle factors on cognitive function: a cross-sectional study.

BACKGROUND: Frailty describes an age-related state of deterioration in biological function. This study aimed to investigate the association between frailty and cognitive function and its combined effects with lifestyles. METHODS: A total of 3,279 participants from the Dongfeng-Tongji (DFTJ) cohort were tested the cognitive function by using the Chinese version of Mini-mental State Examination (MMSE). Frailty was evaluated based on a 35-item frailty index (FI). Frailty status was dichotomized into robust (FI < 0.15) and frail (FI ≥ 0.15). Multivariate generalized linear regression models and logistic regression models were used to estimate the associations of frailty with MMSE score and cognitive impairment. We also analysed the modification and combined effects of lifestyle factors, including smoking status, drinking status, and regular physical exercise, on the above associations. RESULTS: FI was significantly associated with lower MMSE score [ß (95%Cl) = -0.28 (-0.43, -0.13)] and cognitive impairment [OR (95%Cl) = 1.19 (1.04, 1.35)]. The association of frailty status with MMSE were found to be stronger among ever smokers [ß(95%Cl) = -1.08 (-1.64, -0.51)] and physical inactive individuals [ß(95%Cl) = -1.59 (-2.63, -0.54)] while weaker or not significant among never smokers [ß(95%Cl) = -0.30 (-0.62, 0.01)] and physical active individuals [ß(95%Cl) = -0.37 (-0.65, -0.08))]. There were significant combined effects of frailty status with unhealthy lifestyles including smoking, alcohol drinking, and physical inactive on cognitive impairment. CONCLUSIONS: Frailty was associated with cognitive impairment among Chinese middle-aged and elderly people, while smoking cessation and regular physical exercise could attenuate the above associations, which highlight the potential preventive interventions.

Arsenic exposure and its joint effects with cigarette smoking and physical exercise on lung function impairment: Evidence from an occupational cohort study.

BACKGROUND: Arsenic (As) is an established toxic metal, but its effect on longitudinal lung function change among occupational workers is less conclusive. METHODS: 1243 participants were recruited in a coke-oven plant and followed up from 2010 to 2014. Each individual provided 20 mL morning urine sample at baseline, which was then used for urinary levels of As (U-As) and polycyclic aromatic hydrocarbon (PAH) metabolites detecting. Lung function levels at both baseline and the end of follow-up were determined. Multiple linear regression models were used to analyze the associations between U-As with annual lung function changes, and to evaluate the joint effects of U-As with cigarette smoking and regular physical exercise. RESULTS: Among all participants, each 2-fold increase in U-As was associated with -12.09 (95%CI: -19.37, -4.81) mL, -0.32% (95%CI: -0.54%, -0.10%), -15.04 (95%CI: -24.62, -5.46) mL, and -0.36% (95%CI: -0.64%, -0.08%) annual changes in reduced forced expiratory volume in 1 second (FEV1), percent predicted FEV1 (ppFEV1), forced vital capacity (FVC), and percent predicted FVC (ppFVC), respectively. These effects were more pronounced among coke-oven workers with smoking (especially heavy smoking with pack-years≥15) and without regular physical exercise. Compared to low-As-exposed (≤4.70 µg/mmol creatinine) non-smokers with regular physical exercise, the high-As-exposed (>4.70 µg/mmol creatinine) smokers without regular physical exercise had the worst annual declines in FEV1 [ß (95%CI) = -69.01 (-106.67, -31.34) mL], ppFEV1 [ß (95%CI) = -1.94% (-3.02%, -0.87%)], FVC [ß (95%CI) = -78.66 (95%CI: -129.46, -27.86) mL], and ppFVC [ß (95%CI) = -1.80% (-3.23%, -0.37%)]. CONCLUSIONS: The findings in our prospective cohort study suggested the positively linear dose-response relationship of U-As with annual lung function decline. The adverse effects of As could be enhanced by cigarette smoking and attenuated by regular physical exercise. Specific emphasizes on tobacco control and physical exercise were suggested to prevent As exposure induced pulmonary impairment.

[Association of health literacy and screen time with depressive symptoms among middle school students].

OBJECTIVE: To examine the association of health literacy( HL), screen time and depressive symptoms in middle school students. METHODS: In December 2017, a convenient cluster sampling method was used to select all the students from Junior 1 to Senior 3 in a middle school in Shenyang City in the cooperation area as the subjects. And 1062 valid questionnaires were collected, with the use of the group's self-made questionnaire. The average age of the 1062 students was( 15. 38 ± 1. 74) years old, among which 576 boys and 486 girls were surveyed. Questionnaires survey was conducted to collect information on demographics, health literacy, screen time of study day and depressive symptoms. The Chi-square test was performed according to group differences, and multiple Logistic regression model was used to analyze the association of health literacy( including three dimensions of interpersonal relationship, stress management and mental growth) and screen time and their different combinations and depressive symptoms. RESULTS: The detection rate of depressive symptoms among middle school students was 26. 1%( 277/1062). The prevalence of depressive symptoms among students in high school students, low family income and longer screen time was significantly higher than their peers( χ~2 were 15. 090, 10. 510, 4. 832, P < 0. 05). Data from multiple logistic regression analyses showed that low health literacy, longer screen time and low mental growth were positively correlated with depressive symptoms in middle school students( P < 0. 05). In the same level of health literacy, with the increase of screen time, the higher the detection rate of depressive symptoms of middle school students, the highest detection rate of depressive symptoms of middle school students with longer screen time and low health literacy was 51. 7%( 30/58), and the OR value was 5. 741( 95% CI 2. 999-10. 999). CONCLUSION: Health literacy and screen time are related factors of depressive symptoms. The detection rate of depressive symptoms of middle school students with longer screen time and low health literacy is the highest.

Differential effects of ketoconazole, itraconazole and voriconazole on the pharmacokinetics of imatinib and its main metabolite GCP74588 in rat.

The aim of the study was to develop a high performance liquid chromatography method for simultaneous determination of imatinib and CGP74588 in rat serum and study the inhibition effects of ketoconazole, itraconazole and voriconazole on pharmacokinetics of imatinib and CGP74588 in rats. In our study, we found that ketoconazole caused a significant increase (63.4%) in the AUC of imainib and a 28.8% increase in Cmax, which was greater than that of itraconazole but lower than that of voriconazole. When co-administered with voriconazole, pharmacokinetic parameters of imatinib were not significantly altered except for a 36.8% increase in the Cmax of imtinib. The Cmax of CGP74588 was decreased by 55.8% and AUC(0-∞) 49.7%, while the Vz/F and CLz/F values were increased by 1.7-fold and 1.1-fold, respectively. Itraconazole did not significantly influence the pharmacokinetic parameters of imatinib and CGP74588. The difference may be related to the different variation of inhibition sites of the three azole antifungal agents on CYP3A4 and P-gp. In clinical, when imatinib was co-administrated with ketoconazole or voriconazole, dose adjustment of imatinib should be taken into account.

Investigation of the Role of K2SO4 Electrolyte in Hole Transport Layer for Efficient Quasi-2D Perovskite Light-Emitting Diodes.

Quasi-two-dimensional (2D) perovskite light-emitting diodes are promising light sources for color display and lighting. However, poor carrier injection and transport between the bottom hole transport layer (HTL) and perovskite limit the device performance. Here we demonstrate a simple and effective way to modify the HTL for enhancing the performance of perovskite light-emitting diodes (PeLEDs). An electrolyte K2SO4 is used to mix with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) as the hole transport layer. The K+ doping helped the quasi-2D perovskite phases grow vertically along the interface of the PEDOT:PSS, fine-modulate the phase distribution, and simultaneously reduce the defect density of quasi-2D perovskites. It also significantly reduced the exciton quenching and injection barrier at PEDOT:PSS and quasi-2D perovskite interface. The optimized green PeLEDs with the K2SO4 doped PEDOT:PSS HTL showed a maximum luminance of 17185 cd/m2 which is almost 4.7 times brighter than the control one, with a maximum external quantum efficiency of 18.64%.

Mitochondrial DNA copy number mediated the associations between perfluoroalkyl substances and breast cancer incidence: A prospective case-cohort study.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, ß(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study.

Mosaic loss of chromosome Y (mLOY) is the most common somatic alteration as men aging and may reflect genome instability. PM exposure is a major health concern worldwide, but its effects with genetic factors on mLOY has never been investigated. Here we explored the associations of PM2.5 and PM10 exposure with mLOY of 10,158 males measured via signal intensity of 2186 probes in male-specific chromosome-Y region from Illumina array data. The interactive and joint effects of PM2.5 and PM10 with genetic factors and smoking on mLOY were further evaluated. Compared with the lowest tertiles of PM2.5 levels in each exposure window, the highest tertiles in the same day, 7-, 14-, 21-, and 28-day showed a 0.005, 0.006, 0.007, 0.007, and 0.006 decrease in mLRR-Y, respectively (all P < 0.05), with adjustment for age, BMI, smoking pack-years, alcohol drinking status, physical activity, education levels, season of blood draw, and experimental batch. Such adverse effects were also observed in PM10-mLOY associations. Moreover, the unweighted and weighted PRS presented significant negative associations with mLRR-Y (both P < 0.001). Participants with high PRS and high PM2.5 or PM10 exposure in the 28-day separately showed a 0.018 or 0.019 lower mLRR-Y level [ß (95 %CI) = -0.018 (-0.023, -0.012) and - 0.019 (-0.025, -0.014), respectively, both P < 0.001], when compared to those with low PRS and low PM2.5 or PM10 exposure. We also observed joint effects of PM with smoking on exacerbated mLOY. This large study is the first to elucidate the impacts of PM2.5 exposure on mLOY, and provides key evidence regarding the interactive and joint effects of PM with genetic factors on mLOY, which may promote understanding of mLOY development, further modifying and increasing healthy aging in males.

Associations of ambient air pollution exposure and lifestyle factors with incident dementia in the elderly: A prospective study in the UK Biobank.

OBJECTIVE: Dementia is an important disease burden among the elderly, and its occurrence may be profoundly affected by environmental factors. Evidence of the relationship between air pollution and dementia is emerging, but the extent to which this can be offset by lifestyle factors remains ambiguous. METHODS: This study comprised 155,828 elder adults aged 60 years and above in the UK Biobank who were dementia-free at baseline. Cox proportional hazard models were conducted to examine the associations of annual average levels of air pollutants in 2010, including nitrogen dioxide (NO2), nitrogen oxides (NOX), particulate matter (PM2.5, PM10, and PMcoarse) and lifestyle factors recorded at baseline [physical activity (PA), sleep patterns, or smoking status] with incident risk of dementia, and their interactions on both multiplicative and additive scales. RESULTS: During a 12-year period of follow-up, 4,389 incidents of all-cause dementia were identified. For each standarddeviationincrease in ambient NO2, NOX or PM2.5, all-cause dementia risk increases by 1.07-fold [hazard ratio (HR) and 95 % confidence interval (CI) = 1.07 (1.04, 1.10)], 1.05-fold (95 % CI: 1.02, 1.08) and 1.07-fold (95 % CI: 1.04, 1.10), whereas low levels of PA, poor sleep patterns, and smoking are associated with an elevated risk of dementia [HR (95 % CI) = 1.17 (1.09, 1.26), 1.13 (1.00, 1.27), and 1.14 (1.07, 1.21), respectively]. Furthermore, these air pollutants show joint effects with low PA, poor sleep patterns, and smoking on the onset of dementia. The moderate to high levels of PA could significantly or marginally significantly modify the associations between NO2, NOX or PM2.5 (P-int = 0.067, 0.036, and 0.067, respectively) and Alzheimer's disease (AD), but no significant modification effects are found for sleep patterns or smoking status. CONCLUSION: The increased exposures of NO2, NOX, or PM2.5 are associated with elevated risk of dementia among elderly UK Biobank population. These air pollutants take joint effects with low PA, poor sleep patterns, and smoking on the development of dementia. In addition, moderate to high levels of PA could attenuate the incident risk of AD caused by air pollution. Further prospective researches among other cohort populations are warranted to validate these findings.

DNA methylation aging signatures of multiple metals exposure and their mediation effects in metal-associated mortality: Evidence from the Dongfeng-Tongji cohort study.

Humans were exposed to multiple metals, but the impact of metals on DNA methylation-age (DNAm-age), a well-recognized aging measure, remains inconclusive. This study included 2942 participants from the Dongfeng-Tongji cohort. We detected their plasma concentrations of 23 metals and determined their genome-wide DNA methylation using the Illumina Human-MethylationEPIC BeadChip. Five DNAm-age acceleration indexes (DAIs), including HannumAge-Accel, HorvathAge-Accel, PhenoAge-Accel, GrimAge-Accel (residual from regressing corresponding DNAm-age on chronological age) and DNAm-mortality score (DNAm-MS), were separately calculated. We found that each 1-unit increase in ln-transformed copper (Cu) was associated with a separate 1.02-, 0.83- and 0.07-unit increase in PhenoAge-Accel, GrimAge-Accel, and DNAm-MS (all FDR<0.05). Each 1-unit increase in ln-transformed nickel (Ni) was associated with a 0.34-year increase in PhenoAge-Accel, while each 1-unit increase in ln-transformed strontium (Sr) was associated with a 0.05-unit increase in DNAm-MS. The Cu, Ni and Sr showed joint positive effects on above three DAIs. PhenoAge-Accel, GrimAge-Accel, and DNAm-MS mediated a separate 6.5%, 12.3%, 6.0% of the positive association between Cu and all-cause mortality; GrimAge-Accel mediated 14.3% of the inverse association of selenium with all-cause mortality. Our findings revealed the effects of Cu, Ni, Sr and their co-exposure on accelerated aging and highlighted mediation roles of DNAm-age on metal-associated mortality.

Associations between multiple metals exposure and biological aging: Evidence from the Dongfeng-Tongji cohort.

Aging is related to a progressive decline in physiological functions and is affected by environmental factors. Metal exposures are linked with many health effects, but have poorly understood associations with aging. In this study, a total of 33,916 participants from the Dongfeng-Tongji cohort were included to establish biological age (BA) predictors by using recent advanced algorithms, Klemera and Doubal method (KDM) and Mahalanobis distance. Two biological aging indexes (BAIs), recorded as KDM-accel [the residual from regressing KDM-BA on chronological age] and physiological dysregulation (PD), were separately defined and tested on their associations with mortality by using Cox proportional hazard models. Among 3320 subjects with laboratory determinations of 23 metals in plasma, the individual and overall associations between these metals and BAIs were evaluated by using multiple-linear regression and weighted quantile sum (WQS) models. Both BAIs were prospectively associated with all-cause mortality among the whole participants [KDM-accel: HR(95%CI) = 1.23(1.18, 1.29); PD: HR(95%CI) = 1.37(1.31, 1.42)]. Each 1-unit increment in ln-transformed strontium and molybdenum were cross-sectionally associated with a separate 0.71- and 0.34-year increase in KDM-accel, and each 1 % increment in copper, rubidium, strontium, cobalt was cross-sectionally associated with a separate 0.10 %, 0.10 %, 0.09 %, 0.02 % increase in PD (all FDR < 0.05). The WQS models observed mixture effects of multi-metals on aging, with a 0.20-year increase in KDM-accel and a 0.04 % increase in PD for each quartile increase in ln-transformed concentrations of all metals [KDM-accel: ß(95%CI) = 0.20(0.08, 0.32); PD: ß(95%CI) = 0.04(0.02, 0.06)]. Our findings revealed that plasma strontium, molybdenum, copper, rubidium and cobalt were associated with accelerated aging. Multi-metals exposure showed mixture effects on the aging process, which highlights potential preventative interventions.

Associations of exposure to perfluoroalkyl substances with serum uric acid change and hyperuricemia among Chinese women: Results from a longitudinal study.

BACKGROUND: Cross-sectional studies have reported associations of perfluorooctanoic acid (PFOA) with concurrent serum uric acid (UA) levels. However, the prospective associations of other commonly detected perfluoroalkyl substances (PFASs) with serum UA and hyperuricemia remain unclear. METHODS: A total of 654 females from the Dongfeng-Tongji cohort, who were followed up from 2008 to 2018, were included in this study. We measured their baseline plasma concentrations of six PFASs [including perfluorooctane sulfonic acid (PFOS), PFOA, perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluoroheptanoic acid (PFHpA)], as well as their serum UA levels at both baseline and follow-up visits. General linear and logistic regression models were constructed to explore the associations of each PFAS with annual change of serum UA and incident hyperuricemia. Mixture effects of PFASs were further assessed by using the quantile g-computation approach. RESULTS: Compared to participants with low PFNA exposure (≤50th), those with high PFNA exposure (>75th) had significantly increased annual increment of serum UA [ß(95%CI) = 2.58 (0.60, 4.55)]. No significant associations of PFOS, PFOA, PFDA, PFHxS, or PFHpA with serum UA change were observed. Besides, females with high PFOA or PFHpA (>75th) exposure had higher incident risk of hyperuricemia than those with low exposure (<50th) [OR (95%CI) = 1.94 (1.00, 3.76) and 1.86 (1.03, 3.36), respectively]. No significant associations of PFOS, PFNA, PFDA, and PFHxS with hyperuricemia risk were observed. Quantile g-computation approach didn't find significant effects of PFAS co-exposure on serum UA change or hyperuricemia incidence. CONCLUSIONS: Our findings suggested exposure to PFASs as a risk factor for hyperuricemia and shed light on hyperuricemia prevention for elderly females.

Age-related DNA methylation on Y chromosome and their associations with total mortality among Chinese males.

In view of the sex differences in aging-related diseases, sex chromosomes may play a critical role during aging process. This study aimed to identify age-related DNA methylation changes on Y chromosome (ChrY). A two-stage study design was conducted in this study. The discovery stage contained 419 Chinese males, including 205 from the Wuhan-Zhuhai cohort panel, 107 from the coke oven workers panel, and 107 from the Shiyan panel. The validation stage contained 587 Chinese males from the Dongfeng-Tongji sub-cohort. We used the Illumina HumanMethylation BeadChip to determine genome-wide DNA methylation in peripheral blood of the study participants. The associations between age and methylation levels of ChrY CpGs were investigated by using linear regression models with adjustment for potential confounders. Further, associations of age-related ChrY CpGs with all-cause mortality were tested in the validation stage. We identified the significant associations of 41 ChrY CpGs with age at false discovery rate (FDR) <0.05 in the discovery stage, and 18 of them were validated in the validation stage (p < 0.05). Meta-analysis of both stages confirmed the robust positive associations of 14 CpGs and negative associations of 4 CpGs with age (FDR<0.05). Among them, cg03441493 and cg17816615 were significantly associated with all-cause mortality risk [HR(95% CI) = 1.37 (1.04, 1.79) and 0.70 (0.54, 0.93), respectively]. Our results highlighted the importance of ChrY CpGs on male aging.

Epigenome-wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk.

Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub-cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10-5 and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%∼22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.

Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: A case-cohort study in the Dongfeng-Tongji cohort.

Experimental studies have suggested perfluoroalkyl substances (PFASs) as mammary toxicants, but few studies evaluated the prospective associations of PFASs with breast cancer risk. We performed a case-cohort study within the Dongfeng-Tongji cohort, including incident breast cancer cases (n = 226) and a random sub-cohort (n = 990). Baseline plasma concentrations of four perfluorinated carboxylic acids (PFCAs) [perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroheptanoic acid (PFHpA)] and two perfluorinated sulfonic acids (PFSAs) [perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)] were measured. Barlow-weighted Cox regression models revealed that each 1-unit increase in ln-transformed PFOA and PFHpA was associated with a separate 35% and 20% elevated incident risk of breast cancer [HR(95%CI) = 1.35(1.03, 1.78) and 1.20(1.02, 1.40), respectively], which were also significant among postmenopausal females [HR(95%CI) = 1.34(1.01, 1.77) and 1.23 (1.02, 1.48), respectively]. Quantile g-computation analysis observed a 19% increased incident risk of breast cancer along with each simultaneous quartile increase in all ln-transformed PFCA concentrations [HR(95%CI) = 1.19(1.01, 1.41)], with PFOA accounting for 56% of the positive effect. Our findings firstly revealed the impact of short-chain PFHpA on increased incident risk of breast cancer, suggested exposure to PFASs as a risk factor for breast cancer, and shed light on breast cancer prevention by regulating PFASs as a chemical class.

Metabolic linkages between zinc exposure and lung cancer risk: A nested case-control study.

Epidemiologic studies have suggested that elevated concentrations of zinc are associated with a decreased risk of lung cancer, but the underlying mechanisms remain to be investigated. The metabolites are highly sensitive to environmental stress, which will help to reveal the linkages between zinc exposure and lung cancer risk. We designed a nested case-control study including 101 incident lung cancer cases and 1:2 age- and sex-frequency-matched 202 healthy controls from the Dongfeng-Tongji (DFTJ) cohort. Their plasma level of zinc was determined by using inductively coupled plasma-mass spectrometry (ICP-MS) and plasma profiles of metabolites were detected by using an untargeted metabolomics approach. The generalized linear models (GLM) were applied to assess the associations of plasma zinc with metabolites, and the mediation effects of zinc-related metabolites on zinc-lung cancer association were further testified. The concentrations of 55 metabolites had linear dose-response relationships with plasma zinc at a false discovery rate (FDR) < 0.05, among which L-proline, phosphatidylcholine (PC, 34:2), phosphatidylethanolamine (PE, O-36:5), L-altrose, and sphingomyelin (SM, 40:3) showed different levels between lung cancer cases and healthy controls (fold change = 0.92, 0.95, 1.07, 0.90, and 1.08, respectively, and all P < 0.05). The plasma concentration of SM(40:3) was negatively associated with incident risk of lung cancer [OR(95%CI) = 0.71(0.55, 0.91), P = 0.007] and could mediate 41.7% of the association between zinc and lung cancer risk (P = 0.004). Moreover, compared to the traditional factors, addition of SM(40:3) exerted improved prediction performance for incident risk of lung cancer [AUC(95%CIs) = 0.714(0.654, 0.775) vs. 0.663(0.600, 0.727), P = 0.030]. Our findings revealed metabolic profiles with zinc exposure and provide new insight into the alternations of metabolites underpinning the links between zinc exposure and lung cancer development.