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.

Associations between multiple metals exposure and cognitive function in the middle-aged and older adults from China: A cross-sectional study.

The rapidly rising risk of cognitive decline is a serious challenge for the elderly. As the wide-distributed environmental chemicals, the effects of metals exposure on cognitive function have attracted much attention, but the results remain inclusive. This study aimed to investigate the roles of multiple metals co-exposure on cognition. We included a total of 6112 middle-aged and older participants, detected their plasma levels of 23 metals by using inductively coupled plasma mass spectrometry, and assessed their cognitive function by using the Mini-Mental State Examination (MMSE). The results showed that increased plasma levels of iron (Fe) and zinc (Zn) were positively associated with MMSE score, but the increased levels of nickel (Ni) and lead (Pb) were associated with decreased MMSE score (all FDR < 0.05). Subjects exposed to both high levels of Ni and Pb showed the lowest MMSE score [ß (95% CI) = -0.310 (-0.519, -0.100)], suggesting that Ni and Pb had a synergistic toxic effect on cognitive function. In addition, the hazardous roles of Ni and Pb were mainly found among subjects with low plasma level of Zn, but were not significant among those with high-Zn level [Ni: ß (95% CI) = -0.281 (-0.546, -0.015) vs. -0.146 (-0.351, 0.058); Pb: ß (95% CI) = -0.410 (-0.651, -0.169) vs. -0.060 (-0.275, 0.155)], which suggested that Zn could attenuate the adverse effects of Pb and Ni on cognitive function. The cognitive function was gradually decreased among subjects with increased number of adverse exposures to the above four metals (Ptrend < 0.001). In conclusion, our findings revealed the individual, interactive, and combined effects of Fe, Ni, Pb, and Zn on cognitive function, which may provide new perspectives on cognitive protection, but further prospective cohort studies and biological researches are needed to validate these findings.

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.

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.

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.

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 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.

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.

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.

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.

Downregulated Tim-3 expression is responsible for the incidence and development of colorectal cancer.

The present study aimed to investigate the role of T cell immunoglobulin domain and mucin-3 (Tim-3) in its gene and protein forms in colorectal cancer (CRC), and to verify the significance of Tim-3 expression in patients with CRC. A prospective analysis of 258 patients with CRC and 246 normal controls was conducted between December 2012 and June 2015. Intestinal samples were collected, including of CRC tissues, paracancerous tissues and normal colon mucosa tissues. Peripheral venous blood samples were also collected. Polymerase chain reaction (PCR) amplification, reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis was performed for the detection and evaluation of Tim-3 gene and protein in various tissues. PCR analysis indicated that the T and G alleles of -882C/T and 4259T/G are associated with a significantly increased risk of CRC. Following the confirmation of Tim-3 expression in CRC tissues, RT-qPCR detection and western blot analysis revealed clear downregulation of Tim-3 mRNA and protein expression in the blood and tissue samples obtained from patients with CRC, as compared with in the corresponding control samples. Similar trends of decreased Tim-3 mRNA levels and protein expression were observed in CRC tissues compared with in the paracancerous and the normal colon mucosa tissues. In addition, the mRNA and protein expression levels in the paracancerous tissues were lower than those in the normal colon mucosa tissues. Furthermore, significantly lower Tim-3 mRNA levels were observed in patients with a tumor size >5 cm, a poor differentiation degree, higher tumor-node-metastasis stage (stage III-IV), and lymph node and distant metastasis. Collectively, genetic changes to Tim-3, expressed as polymorphisms in Tim-3, and decreased mRNA/protein expression may be partially responsible for the incidence and development of CRC.