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The effects of environmental polycyclic aromatic hydrocarbons (PAHs) exposure on glycemic regulation and the underlying genetic mechanism were still unclear. This study aimed to analyze the longitudinal joint effects of PAHs exposure and genetic susceptibility on fasting plasma glucose (FPG) through a longitudinal study. We included 4104 observations (2383 baseline participants and 1721 6-year follow-up participants) from Wuhan-Zhuhai cohort. Ten urinary PAHs metabolites and FPG were measured at both baseline and follow-up. We constructed the polygenic risk scores (PRS) of FPG from the corresponding genome-wide association studies. Linear mixed models were used to explore the associations of urinary PAHs metabolites or FPG-PRS on FPG levels in the repeated-measure analysis. Besides, the longitudinal relationships of urinary PAHs metabolites, FPG-PRS, and their joint effects on FPG change over 6 years were evaluated by linear regression models. Compared with participants with persistent low levels of urinary total PAHs metabolites, hydroxynaphthalene, and hydroxyphenanthrene, participants with persistent high levels had average decreases of 0.180, 0.200, and 0.261 mmol/L for FPG change over 6 years, respectively. Each 1-unit increase of FPG-PRS was associated with a 0.521 mmol/L for FPG change over 6 years. Besides, compared with participants with high FPG-PRS and persistent low levels of urinary total hydroxynaphthalene, hydroxyfluorene, and hydroxyphenanthrene, participants with low FPG-PRS and persistent high levels had average decreases of 0.330, 0.557, and 0.421 mmol/L for FPG change over 6 years. Our findings demonstrated that high-level PAHs exposure was longitudinally associated with an average decrease of FPG over 6 years, and low FPG genetic risk can enhance the above associations. Our findings emphasized the hypoglycemic effect of PAHs exposure, shed new light on the complex effects between PAHs exposure and genetic factors in the prevention of high FPG, and might provide some clues for the development of potential hypoglycemic agents., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

To quantify the association of polycyclic aromatic hydrocarbons (PAHs) and the polygenic risk score (PRS) with lung function decline, we developed a repeated-measures study with 4681 observations from baseline and 6-year follow-up of the Wuhan-Zhuhai cohort. Lung function and urinary monohydroxylated PAH metabolites (OH-PAHs) were measured for each observation. The PRS was derived from 246 lung function-associated genetic variants weighted by the effect size of the decreasing ratio of forced expiratory volume in 1 s by forced vital capacity (FEV1/FVC). Linear mixed models were used to estimate the longitudinal exposure-response relationships between OH-PAHs and lung function, and to evaluate the interactions between OH-PAHs and PRS on the longitudinal change of lung function. We found that each 1-unit increase in log-transformed values of 9-hydroxyfluorene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 9-hydroxyphenanthrene, 2-hydroxyphenanthrene, 1-hydroxyphenanthrene, 1-hydroxypyrene, low molecular weight OH-PAHs (ΣLMW-OH-PAHs), and total OH-PAHs (ΣOH-PAHs) was associated with an annual change in FEV1/FVC of -0.140, -0.112, -0.260, -0.300, -0.159, -0.220, -0.145, -0.156, and -0.177 %/year, respectively. Interactions on the annual decline of FEV1/FVC were detected between ΣLMW-OH-PAHs and PRS (-0.010 %/year, 95% confidence interval -0.018 to -0.001, P int  = 0.0228), and between ΣOH-PAHs and PRS (-0.010 %/year, -0.018 to -0.001, P int  = 0.0203). These results indicated that specific and total urinary OH-PAHs were associated with the longitudinal FEV1/FVC decline, and ΣLMW-OH-PAHs as well as ΣOH-PAHs interacted with PRS on the annual decline of FEV1/FVC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

The effects of triazine herbicides on glucose metabolism remain unclear. In this study, we aimed to assess the associations between serum triazine herbicides and glycemia-related risk indicators in general adults, and to evaluate the mediating role of natural immunoglobulin M antibodies (IgM) in the above associations among uninfected participants. We measured the concentrations of atrazine, cyanazine, and IgM in serum, as well as fasting plasma glucose (FPG), and fasting plasma insulin in 4423 adult participants from the Wuhan-Zhuhai cohort baseline population, enrolled in 2011-2012. Generalized linear models were used to evaluate the associations of serum triazine herbicides with glycemia-related risk indicators, and mediation analyses were performed to evaluate the mediating role of serum IgM in the above associations. The median levels of serum atrazine and cyanazine were 0.0237 μg/L and 0.0786 μg/L, respectively. Our study found significant positive associations of serum atrazine, cyanazine, and Σtriazine with FPG levels, risk of impaired fasting glucose (IFG), abnormal glucose regulation (AGR), and type 2 diabetes (T2D). Additionally, serum cyanazine and Σtriazine were found to be significant positive associated with the homeostatic model assessment of insulin resistance (HOMA-IR) levels. Significant negative linear relationships were observed in associations of serum IgM with serum triazine herbicides, FPG, HOMA-IR levels, the prevalence of T2D, and AGR (P < 0.05). Furthermore, we observed a significant mediating role by IgM in the associations of serum triazine herbicides with FPG, HOMA-IR, and AGR, with the proportions ranging from 2.96% to 7.71%. To ensure the stability of our findings, we conducted sensitivity analyses in normoglycemic participants and found that the association of serum IgM with FPG and the mediating role by IgM remained stable. Our results suggest that triazine herbicides exposure is positively associated with abnormal glucose metabolism, and decreasing serum IgM may partly mediate these associations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The adverse health effects of ozone pollution have been a globally concerned public health issue. Herein we aim to investigate the association between ozone exposure and glucose homeostasis, and to explore the potential role of systemic inflammation and oxidative stress in this association. A total of 6578 observations from the Wuhan-Zhuhai cohort (baseline and two follow-ups) were included in this study. Fasting plasma glucose (FPG) and insulin (FPI), plasma C-reactive protein (CRP, biomarker for systemic inflammation), urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG, biomarker for oxidative DNA damage), and urinary 8-isoprostane (biomarker for lipid peroxidation) were repeatedly measured. After adjusting for potential confounders, ozone exposure was positively associated with FPG, FPI, and homeostasis model assessment of insulin resistance (HOMA-IR), and negatively associated with HOMA of beta cell function (HOMA-β) in cross-sectional analyses. Each 10 ppb increase in cumulative 7-days moving average ozone was associated with a 13.19%, 8.31%, and 12.77% increase in FPG, FPI, and HOMA-IR, respectively, whereas a 6.63% decrease in HOMA-β (all P < 0.05). BMI modified the associations of 7-days ozone exposure with FPI and HOMA-IR, and the effects were stronger in subgroup whose BMI ≥24 kg/m 2 . Consistently high exposure to annual average ozone was associated with increased FPG and FPI in longitudinal analyses. Furthermore, ozone exposure was positively related to CRP, 8-OHdG, and 8-isoprostane in dose-response manner. Increased CRP, 8-OHdG, and 8-isoprostane could dose-dependently aggravate glucose homeostasis indices elevations related to ozone exposure. Increased CRP and 8-isoprostane mediated 2.11-14.96% of ozone-associated glucose homeostasis indices increment. Our findings suggested that ozone exposure could cause glucose homeostasis damage and obese people were more susceptible. Systemic inflammation and oxidative stress might be potential pathways in glucose homeostasis damage induced by ozone exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

PM 2.5 exposure leads to lung function alteration. The potential pathway underlying above association, especially the role of DNA methylation is unclear. The objectives of this study are to evaluate the associations of personal PM 2.5 concentrations with DNA methylation at the epigenome-wide level, and investigate how PM 2.5 -related DNA methylation affects lung function. A total of 402 observations of non-smokers were selected from the Wuhan-Zhuhai cohort. PM 2.5 exposure was estimated through a model established in the same population. Blood DNA methylation levels were determined through Illumina Infinium MethylationEPIC BeadChips. Lung function was tested through spirometry on the day of blood sampling. The associations of PM 2.5 exposure with DNA methylation and DNA methylation with lung function were determined through linear mixed models. Ten PM 2.5 -related CpG sites (mapped to 7 different genes) were observed with false discovery rate <0.05. Methylation levels of cg24821877, cg24862131, cg23530876, cg11149743 and cg10781276 were positively associated with PM 2.5 concentrations. While methylation levels of cg10314909, cg08968107, cg18362281, cg24663971 and cg17834632 were negatively associated with PM 2.5 concentrations. The top CpG was cg24663971 (P = 1.51✕10 -9 ). Among the above 10 sites, significantly positive associations of methylation levels of cg24663971 with FVC%pred and FEV 1 %pred, and cg10314909 with FVC, FVC%pred, and FEV 1 %pred were observed. Age had modification effect on the associations between cg24663971 methylation and FVC%pred, and the associations were more obvious among participants with age ≥58 years. In conclusion, PM 2.5 exposure was associated with DNA methylation, and PM 2.5 -related DNA methylation was associated with lung function among Wuhan urban non-smokers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

As a polycyclic aromatic hydrocarbon, environmental exposure to phenanthrene is widespread worldwide. The potential effects and mechanism of phenanthrene exposure on fasting plasma glucose (FPG) have not been well determined. In this study, we aim to explore the effects of phenanthrene exposure and AMER3 variants on fasting plasma glucose (FPG) through a longitudinal epidemiological study. Repeated measurements of five urinary hydroxyphenanthrene (OHPh) for 5739 participants with 7083 observations from the Wuhan-Zhuhai cohort were performed to analyze the relationships between total OHPh (ΣOHPh) and FPG using linear mixed models and restricted cubic spline functions. Then, we genotyped 2777 participants (4104 observations) using the Infinium OmniZhongHua-8 BeadChip and included all 14 single nucleotide polymorphisms (SNPs) within the AMER3 gene to analyze the interaction of the AMER3 on the relationship between ΣOHPh and FPG. We observed a U-shaped relationship between ΣOHPh and FPG, and the turning point of ΣOHPh was 2.512 μg/mmol Cr. When lower than the turning point, ΣOHPh was negatively associated with FPG, while higher than the turning point, ΣOHPh was positively associated with FPG. Furthermore, we observed interactions (P int <0.05) between two common variants (rs72854995 and rs72854999) of the AMER3 and ΣOHPh on FPG change: the U-shaped relationship was still observed in the GG genotype groups but not in the allele A carriers. Our results suggested that the AMER3 gene can modify the U-shaped relationship between phenanthrenes exposure and FPG, which showed a new gene-environment interaction and will provide a new perspective on the relationship between phenanthrene exposure and FPG., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Environmental risk factors have been implicated in adverse health effects. Previous epidemiological studies on environmental risk factors mainly analyzed the impact of single pollutant exposure on health, while in fact, humans are constantly exposed to a complex mixture consisted of multiple pollutants/chemicals. In recent years, environmental epidemiologists have sought to assess adverse health effects of exposure to multi-pollutant mixtures based on the diversity of real-world environmental pollutants. However, the statistical challenges are considerable, for instance, multicollinearity and interaction among components of the mixture complicate the statistical analysis. There is currently no consensus on appropriate statistical methods. Here we summarized the practical statistical methods used in environmental epidemiology to estimate health effects of exposure to multi-pollutant mixture, such as Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regressions, shrinkage methods (least absolute shrinkage and selection operator, elastic network model, adaptive elastic-net model, and principal component analysis), environment-wide association study (EWAS), etc. We sought to review these statistical methods and determine the application conditions, strengths, weaknesses, and result interpretability of each method, providing crucial insight and assistance for addressing epidemiological statistical issues regarding health effects from multi-pollutant mixture., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Polycyclic aromatic hydrocarbon (PAH) exposure has been considered a risk factor for cardiovascular diseases (CVD), whereas possible mechanisms for this association have not been fully understood. This study focused on exploring the potential effect of oxidatively damaged DNA on the relationships between PAH exposure and the 10-year atherosclerotic CVD (ASCVD) risk. Urinary levels of monohydroxy PAH metabolites (OH-PAHs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG, the typical biomarker for oxidatively damaged DNA) were measured among 3052 subjects in the baseline of the Wuhan-Zhuhai cohort. The relationships between urinary OH-PAHs, 8-oxodG and 10-year risk of ASCVD were analyzed by linear mixed models and logistic regression models, respectively. The mediation analysis was further applied to explore the role of 8-oxodG in the relationship between urinary OH-PAHs and 10-year ASCVD risk. After controlling for potential confounders, the log-transformed level of total urinary low molecular weight OH-PAHs (∑LMW OH-PAHs) was significantly associated with an elevated risk of 10-year ASCVD [odds ratio (OR) = 1.222, 95% confidence interval (CI): 1.065-1.402]. More specifically, significantly positive dose-response relationships between total urinary hydroxynaphthalene (∑OHNa), hydroxyfluorene (∑OHFlu), hydroxyphenanthrene (∑OHPh) and 10-year ASCVD risk were observed (all P for trend <0.05). We also found positive relationships between urinary OH-PAH levels and 8-oxodG, as well as between urinary 8-oxodG levels and 10-year risk of ASCVD. Moreover, mediation analyses indicated that urinary 8-oxodG mediated 14.49%, 12.62% and 10.55% of the associations between urinary ∑LMW OH-PAHs, ∑OHNa, ∑OHFlu and 10-year ASCVD risk, respectively. These findings suggest that the oxidatively damaged DNA pathway may be a possible mechanism underlying PAH-associated ASCVD risk elevation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)