Epigenome-wide perspective of cadmium-associated DNA methylation and its mediation role in the associations of cadmium with lipid levels and dyslipidemia risk.

BACKGROUND: Studies demonstrated the associations of cadmium (Cd) with lipid levels and dyslipidemia risk, but the mechanisms involved need further exploration. OBJECTIVES: We aimed to explore the role of DNA methylation (DNAM) in the relationship of Cd with lipid levels and dyslipidemia risk. METHODS: Urinary cadmium levels (UCd) were measured by inductively coupled plasma mass spectrometry, serum high-density lipoprotein (HDL), total cholesterol, triglyceride, and low-density lipoprotein were measured with kits, and DNAM was measured using the Infinium MethylationEPIC BeadChip. Robust linear regressions were conducted for epigenome-wide association study. Multivariate linear and logistic regressions were performed to explore the associations of UCd with lipid levels and dyslipidemia risk, respectively. Mediation analyses were conducted to explore potential mediating role of DNAM in the associations of Cd with lipid levels and dyslipidemia risk. RESULTS: UCd was negatively associated with HDL levels (p = 0.01) and positively associated with dyslipidemia (p < 0.01). There were 92/11 DMPs/DMRs (FDR<0.05) associated with UCd. Cd-associated DNAM and pathways were connected with cardiometabolic diseases and immunity. Cg07829377 (LINC01060) mediated 42.05%/22.88% of the UCd-HDL/UCd-dyslipidemia associations (p = 0.02 and 0.01, respectively). CONCLUSIONS: Cadmium caused site-specific DNAM alterations and the associations of UCd with lipid levels and dyslipidemia risk may be partially mediated by DNAM.

Associations of essential trace elements with epigenetic aging indicators and the potential mediating role of inflammation.

BACKGROUND: Essential trace elements (ETEs) play essential roles in vital functions, but their effects on epigenetic aging remain poorly understood. OBJECTIVES: This study aimed to investigate the associations of ETEs with four epigenetic aging indicators and assess the potential mediating role of inflammation. METHODS: We recruited 93 individuals from hospitals between October 2018 and August 2019. Plasma levels of cobalt, copper, iron, manganese, molybdenum, selenium, and zinc were measured by ICP-MS, and leukocyte DNA methylation levels were measured using Illumina MethylationEPIC beadchip. Linear regression was used to estimate the association between seven plasma ETEs and epigenetic aging indicators. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models were used to evaluate the effect of ETEs mixtures. Inflammatory status was assessed using four systemic inflammation indices (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII)) and three cytokines (IL-4, IL-6, and IL-13). Mediation analysis was performed to explore the role of inflammation in the above associations. RESULTS: Plasma Se levels were significantly negatively associated with DunedinPACE, whereas Cu levels were significantly positively associated with it. Both WQS regression and BKMR models suggested that Se and Cu dominate the effect of the ETEs mixture. MLR and interleukin 6 were significantly and positively associated with DunedinPACE. Further mediation analysis indicated that inflammation partially mediated the association between ETEs and DunedinPACE. DISCUSSION: Plasma Se and Cu levels are closely associated to epigenetic aging, and inflammation might be a potential mechanism underlying this relationship. These findings contribute to the prevention of health hazards associated with population aging.

Urinary arsenic metabolism, genetic susceptibility, and their interaction on type 2 diabetes.

Growing studies investigated the association of arsenic metabolism with type 2 diabetes (T2D), however, the epidemiological evidence is inconsistent. In addition, the interaction of arsenic metabolism-related genetic risk score (GRS)-arsenic on T2D risk was unclear. The present study aimed to evaluate the association of arsenic metabolism efficiency [inorganic arsenic (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA%)] with T2D risk. Moreover, the relationship of GRS and arsenic metabolism efficiency and the interaction of GRS-arsenic on T2D were investigated. Age- and sex-matched new-onset diabetes case-control study derived from the Dongfeng-Tongji cohort was conducted and 996 pairs participants were included in this study. The leave-one-out approach was used to evaluate the association of arsenic metabolism efficiency with T2D risk. The GRS and weight GRS (wGRS) were calculated based on 79 candidate SNPs. We estimated the relationship of GRS with arsenic metabolism efficiency by linear regression model. The interaction of GRS-arsenic on T2D was assessed by adding a multiplicative interaction term (GRS × arsenic) in the logistic regression models. Urinary iAs% was positively associated with T2D risk, and the OR (95% CI) was 1.06 (1.01, 1.12). MMA% and PMI were negatively associated with T2D risk, and the ORs (95% CI) were 0.87 (0.78, 0.97) and 0.64 (0.47, 0.86), respectively. Urinary DMA, As3+, and As5+ were positively associated with T2D risk. Similar relationships were found between arsenic metabolites and levels of FPG and HbA1c. Moreover, arsenic metabolism-related GRS/wGRS was positively associated with MMA% but negatively associated with DMA%. Genetic predisposition to arsenic metabolism modified the association of inorganic arsenic with T2D risk (Pinteraction = 0.033). Taken together, lower arsenic primary metabolism efficiency (higher iAs% and lower MMA%) may increase T2D risk. Genetic predisposition to arsenic metabolism was associated with arsenic metabolism efficiency, and might modify the association of inorganic arsenic with T2D risk.

Circulating organochlorine pesticide levels, genetic predisposition and the risk of incident type 2 diabetes.

Persistent organochlorine pesticide (OCP) has been associated with type 2 diabetes (T2D), and genetic polymorphism might modify such an association. However, prospective evidence remains scarce. We conducted a nested case-control study comprising 1006 incident diabetic cases and 1006 matched non-diabetic controls [sex and age (±5 years)] from 2008 to 2013 (mean follow-up period: ∼4.6 years) based on the Dongfeng-Tongji cohort in Shiyan City of China, determined baseline levels of nineteen OCPs, and examined the associations of circulating OCPs, both individually and collectively, with incident T2D risk. We also constructed overall genetic risk score (GRS) based on 161 T2D-associated variants and five pathway-specific cluster GRSs based on established variants derived from the Asian population. Compared with the first quartile of serum ß-BHC levels, the multivariable-adjusted ORs (95% CIs) of incident T2D risk in the second, third, and fourth quartiles were 0.98 (0.70-1.39), 1.43 (0.99-2.07), and 1.75 (1.14-2.68), respectively (FDR-adjusted Ptrend = 0.03). A positive association was observed between serum OCP mixture and incident T2D risk and can be largely attributed to ß-BHC. Furthermore, serum ß-BHC and p,p'-DDE showed significant interactions with the GRS for lipodystrophy, a T2D-related pathway representing fat redistribution to viscera, on T2D risk (Pinteraction < 0.05). In conclusion, higher circulating OCP levels were independently associated with an increased risk of T2D, with ß-BHC possibly being the major contributor. Genetic predisposition to T2D-related morbidity, such as visceral adiposity, should be considered when assessing the risk of T2D conferred by OCPs.

Association of serum phthalates exposure with incident type 2 diabetes risk in Chinese population: A nested case-control study.

Prospective epidemiological evidence was lacking on the association of phthalates (PAEs) exposure with incident type 2 diabetes mellitus (T2DM) risk. In present nested case-control study, we identified 1006 T2DM cases and matched 1006 controls based on Dongfeng-Tongji cohort study, and 6 PAEs were detected in baseline serum. The conditional logistic regression model, Bayesian kernel machine regression (BKMR) model and Quantile-based g-computation were applied to evaluate the associations of determined PAEs, either as individuals or as a mixture, with incident T2DM risk. Subgroup analysis was conducted to identify the potential sensitive population of PAEs effects on T2DM. After multiple adjustment, no statistically significant association was observed between single or mixture of PAEs and incident T2DM risk in the whole population. However, serum levels of Di-n-butyl phthalate (DnBP) [OR= 2.06; 95% CI: (1.11-3.96)], Σdibutyl phthalate (ΣDBP) [OR= 1.96; 95% CI: (1.06-3.76)], and Σlow-molecular- weight phthalate (ΣLMW) [OR= 2.27; 95% CI: (1.17-4.57)] were significantly associated with T2DM in current drinker group. Moreover, significant potential interactions were observed among Di-iso-butyl phthalate (DiBP), DnBP, Butyl-benzyl phthalate (BBP), ΣDBP, and ΣLMW with drinking status on T2DM risk (P for interaction = 0.036, 0.005, 0.049. 0.010, and 0.005). We did not find significant associations between serum PAEs levels and T2DM in the whole population. However, current alcohol drinkers expose to higher levels of DnBP, ΣDBP, and ΣLMW had higher risk of T2DM.

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design.

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.

Association between polychlorinated biphenyls exposure and incident type 2 diabetes mellitus: A nested case-control study.

BACKGROUND: Previous epidemiological studies indicated that the association between polychlorinated biphenyls (PCB) and type 2 diabetes mellitus (T2DM) was inconclusive. OBJECTIVE: We investigated the association between PCBs exposure and incident T2DM in a nested case-control study, and further explored the relationship between PCBs and 5-year fasting blood glucose (FBG) changes. METHODS: Baseline concentrations of seven indicator-PCB (PCB-28, 52, 101, 118, 138, 153, 180) were measured in 1006 pairs of incident T2DM cases and matched controls nested within the Dongfeng-Tongji cohort. Conditional logistic regression models and pre-adjusted residuals method were used to assess the associations between PCBs and incident T2DM. We further computed beta coefficients (ßs) of 5-year FBG changes using multivariable generalized linear regression. RESULTS: Non-dioxin-like PCBs (NDL-PCBs) were significantly associated with higher T2DM incidence after adjustment for all covariates. Significant differences were observed for extreme quartiles comparisons (Q4 vs. Q1) of PCBs except PCB-138, and the incidence of T2DM were 1- to 3-fold higher among those in the highest versus lowest PCBs quartiles. Serum NDL-PCBs were positively associated with changes in FBG (P for overall association ≤0.01). Additionally, triglycerides mediated the associations between PCBs and T2DM incidence. CONCLUSION: Our findings showed positive associations of NDL-PCBs with incident T2DM and 5-year FBG changes. PCBs increased incident T2DM via lipid metabolic pathways.

Circulating metals, leukocyte microRNAs and microRNA networks: A profiling and functional analysis in Chinese adults.

BACKGROUND: Metals in the human body represent both environmental exposure and nutritional status. Little is known about the miRNA signature in relation to circulating metals in humans. OBJECTIVES: To characterize metal-associated miRNAs in leukocytes, individually and collectively as networks. METHODS: In a panel of 160 Chinese adults, we measured 23 metals/metalloids in plasma, and sequenced miRNAs and mRNAs in leukocytes. We used linear regression to model the associations between ln-transformed metal concentrations and normalized miRNA levels adjusting for potential confounders. We inferred the enriched leukocyte subtypes for the identified miRNAs using an association approach. We utilized mRNA sequencing data to explore miRNA functions. We also constructed modules to identify metal-associated miRNA networks. RESULTS: We identified 55 metal-associated miRNAs at false discovery rate-adjusted P < 0.05. In particular, we found that lead, nickel, and vanadium were positively associated with potentially lymphocyte-enriched miR-142-3p, miR-150-3p, miR-28-5p, miR-361-3p, and miR-769-5p, and were inversely associated with potentially granulocyte-enriched let-7a/c/d-5p and miR-1294. Interestingly, the five lymphocyte-enriched miRNAs inhibited, whereas miR-1294 activated, ROS and DNA repair pathways. We further confirmed the findings using oxidative damage biomarkers. Next, we clustered co-expressed miRNAs into modules, and identified four miRNA modules that were associated with different metals. The identified modules represented miRNAs enriched in different leukocyte subtypes, and were involved in biological processes including hematopoiesis and immune response, mitochondrial functions, and response to the stimulus. CONCLUSIONS: At commonly exposed low levels, circulating metals were associated with distinct miRNA signatures in leukocytes. The identified miRNAs, individually or as regulatory networks, may provide a mechanistic link between metal exposure and pathophysiological changes in the immune system.

Association of serum bisphenol A levels with incident overweight and obesity risk and the mediating effect of adiponectin.

BACKGROUND: Existing cross-sectional studies indicated a positive association of bisphenol A (BPA) with overweight and obesity. However, the relationship and potential mechanisms underlying this association remain to be elucidated in prospective studies. OBJECTIVE: This study was designed to investigate whether serum BPA is associated with incident overweight and obesity risk, and to further explore whether adiponectin plays a mediating role in the association. METHODS: We measured blood BPA and adiponectin in Chinese populations. The association of serum BPA with overweight and obesity risk was evaluated using multivariable logistic regression models. We further examined the mediating effect of adiponectin by causal mediation analysis. RESULTS: Among 796 participants free of overweight and obesity at baseline, 133 individuals developed overweight and obesity during the follow-up period. Compared with those in the lowest quartile of serum BPA, those in the second and third quartiles were positively associated with incident overweight and obesity risk adjusting for covariates (all P-values < 0.05), whereas this association was not observed in the fourth quartile. Further spline analysis showed an inverted U-shaped dose-response relationship (Pnon-linear = 0.04). Furthermore, each unit of serum log10-transformed BPA levels was associated with higher changes in waist-to-height ratio and body roundness index (all P-values < 0.05). Mediation analysis indicated significant indirect effects of adiponectin on the associations of BPA with overweight and obesity prevalence (mediation proportion: 46.08%; P = 0.02), and BMI levels (mediation proportion: 30.32%; P = 0.03). CONCLUSION: Serum BPA displayed a positive association with incident overweight and obesity risk in a non-monotonic pattern, and adiponectin might mediate the association. Further mechanistic studies are warranted.

Association between serum pyrethroid insecticide levels and incident type 2 diabetes risk: a nested case-control study in Dongfeng-Tongji cohort.

Pyrethroid insecticides have been extensively used worldwide, but few studies explored the prospective association between pyrethroid exposure and incident type 2 diabetes (T2D). We conducted a nested case-control study of 2012 paired cases and controls, and measured eight pyrethroid insecticides in the baseline sera. We used conditional logistic regression models to estimate odds ratios (ORs) with 95% confidence intervals, and constructed multiple-pollutant models to investigate the association of pyrethroid mixture with incident T2D risk. The median concentrations (detection rates) were 3.53 µg/L (92.45%), 0.52 µg/L (99.80%), 1.16 µg/L (90.61%) and 1.43 µg/L (99.95%) for permethrin, cypermethrin, fenvalerate, and deltamethrin, respectively. Compared to participants with serum fenvalerate levels in the first quartile, the multivariable-adjusted ORs of incident T2D were 1.20 (95% CI 0.86-1.67), 1.41 (0.97-2.05), and 2.29 (1.27-4.11) for the second, third and fourth quartile (P trend = 0.01). Spline analysis further confirmed the positive association between serum fenvalerate levels and incident T2D risk (P for overall association = 0.006). Furthermore, mixture models revealed a positive association of pyrethroid mixture with incident T2D risk, with serum fenvalerate ranked as the top contributor (proportion of relative contribution: > 70%). We found that high concentrations of serum pyrethroid insecticides were significantly associated with an increased risk of incident T2D. The elevated risk was largely explained by fenvalerate. Further investigations are urgently needed to confirm our findings and elucidate the underlying mechanisms, given the widespread use of pyrethroids and the global pandemic of diabetes.

NRF2 Genetic Polymorphism Modifies the Association of Plasma Selenium Levels With Incident Coronary Heart Disease Among Individuals With Type 2 Diabetes.

Plasma selenium and NRF2 promoter variants (e.g., rs6721961) are associated with cardiovascular disease risk in the general population. However, epidemiological evidence on the interaction between plasma selenium and NRF2 genetic susceptibility in relation to incident coronary heart disease (CHD) risk remains scarce, especially among individuals with type 2 diabetes (T2D). Thus, we examined whether rs6721961 in the NRF2 gene might modify the association between plasma selenium levels and incident CHD risk among people with T2D. During a mean (SD) follow-up period of 6.90 (2.96) years, 798 incident CHD cases were identified among 2,251 T2D cases. Risk-allele carriers of rs6721961 had a higher risk of incident CHD among people with T2D (adjusted hazard ratio [HR] 1.17; 95% CI 1.02-1.35) versus nonrisk-allele carriers. Each 22.8-µg/L increase in plasma selenium levels was associated with a reduced risk of incident CHD among risk-allele carriers with T2D (HR 0.80; 95% CI 0.71-0.89), whereas no association was found in those without risk alleles (P for interaction = 0.004), indicating that the NRF2 promoter polymorphism might modify the association between plasma selenium levels and incident CHD risk among people with T2D. Our study findings suggest redox-related genetic variants should be considered to identify populations that might benefit most from selenium supplementation. More mechanistic studies are warranted.

The air quality changes and related mortality benefits during the coronavirus disease 2019 pandemic in China: Results from a nationwide forecasting study.

Air quality changes during the coronavirus disease 2019 (COVID-19) pandemic in China has attracted increasing attention. However, more details in the changes, future air quality trends, and related death benefits on a national scale are still unclear. In this study, a total of 352 Chinese cities were included. We collected air pollutants (including fine particulate matter [PM2.5], inhalable particulate matter [PM10], nitrogen dioxide [NO2], and ozone [O3]) data for each city from January 2015 to July 2020. Convolutional neural network-quantile regression (CNN-QR) forecasting model was used to predict pollutants concentrations from February 2020 to January 2021 and the changes in air pollutants were compared. The relationships between the socioeconomic factors and the changes and the avoided mortality due to the changes were further estimated. We found sharp declines in all air pollutants from February 2020 to January 2021. Specifically, PM2.5, PM10, NO2, and O3 would drop by 3.86 µg/m3 (10.81%), 4.84 µg/m3 (7.65%), 0.55 µg/m3 (2.18%), and 3.14 µg/m3 (3.36%), respectively. The air quality changes were significantly related to many of the socioeconomic factors, including the size of built-up area, gross regional product, population density, gross regional product per capita, and secondary industry share. And the improved air quality would avoid a total of 7237 p.m.2.5-related deaths (95% confidence intervals [CI]: 4935, 9209), 9484 p.m.10-related deaths (95%CI: 5362, 13604), 4249 NO2-related deaths (95%CI: 3305, 5193), and 6424 O3-related deaths (95%CI: 3480, 9367), respectively. Our study shows that the interventions to control COVID-19 would improve air quality, which had significant relationships with some socioeconomic factors. Additionally, improved air quality would reduce the number of non-accidental deaths.

Road traffic and air pollution: Evidence from a nationwide traffic control during coronavirus disease 2019 outbreak.

Existing estimations of air pollution from automobile sources are based on either experiments or small-scale governmental interventions. China's nationwide traffic control during the coronavirus disease 2019 outbreak provided us a unique opportunity to assess the direct dose-effect relationship between vehicle density and air pollution. We found that, during the coronavirus disease 2019 outbreak, the nationwide reduced air pollution (except for O3) could be largely explained by traffic control measures. During the traffic control period, every doubling of vehicle density was associated with a decrease of 4.2 (2.0, 6.4) µg/m3 in PM2.5, 5.5 (2.9, 8.1) µg/m3 in PM10, 1.5 (0.9, 2.0) µg/m3 in NO2, and 0.04 (0.02, 0.07) mg/m3 in CO comparing cities with different vehicle densities. Similarly, for every 10% increase in the truck proportion, PM2.5 decreased by 12.3 (4.1, 20.6) µg/m3, PM10 decreased by 14.3 (4.6, 23.9) µg/m3, and CO decreased by 0.14 (0.05, 0.23) mg/m3. Moreover, the associations between vehicle density and reduction in PM2.5, PM10, and CO during the traffic control period were stronger and showed near-complete linearity in cities with low green coverage rate (All P < 0.05 for interaction). According to our estimation, PM2.5 emissions from every doubling of vehicle density can lead to over 8000 excess deaths per year, 66% of which were caused by cardiopulmonary diseases. This natural experiment study is the first to observe the dose-effect relationship between on-road traffic and traffic-generated air pollution, as well as the mitigating effect of urban greening. Findings provide key evidence to the assessment and control of traffic-generated air pollution and its public health impact.