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Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remains unclear. The objectives of this study were to assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships of urinary iron with serum ALT and risk of hyperALT were evaluated by linear mixed model and logistic regression model, respectively. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. This cross-sectional analysis found that urinary iron was positively associated with ALT (β = 0.032; 95% CI: 0.020, 0.044) and hyperALT prevalence (OR = 1.127; 95% CI: 1.065, 1.192). After 3 years of follow-up, participants with persistent high iron levels had increased risk of developing hyperALT (RR = 3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron levels. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) increase and a 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (β = 0.056; 95% CI: 0.039, 0.074) was positively associated with ALT, while the association between 8-OHdG and ALT was insignificant. Furthermore, increased 8-iso-PGF2α significantly mediated 22.48% of the urinary iron-associated ALT increment. Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation. Controlling iron intake and regulating lipid peroxidation may help in preventing liver injury. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Serum samples were measured for atrazine and cyanazine among general urban adults. • Triazine herbicide exposure was associated with abnormal glucose metabolism. • Triazine herbicide exposure was negatively associated with serum IgM level. • Down-regulated serum IgM level was associated with abnormal glucose metabolism. • IgM mediated triazine herbicide exposure-associated abnormal glucose metabolism. [ABSTRACT FROM AUTHOR]

The adverse health effects of pyrethroids exposure have attracted wide concern. We aimed to assess the associations of bifenthrin, a widely used pyrethroid, with glucose homeostasis and risk of type 2 diabetes mellitus (T2DM) and to explore the underlying mechanism. Serum bifenthrin, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and plasma protein carbonyl (PCO) were determined among 3822 participants from the Wuhan-Zhuhai cohort. Glucose homeostasis was evaluated by FPG, FPI, homeostasis model assessment of insulin resistance (HOMA-IR), impaired fasting glucose (IFG), and abnormal glucose regulation (AGR). The associations of serum bifenthrin with glucose homeostasis and risk of T2DM were assessed by generalized linear models and logistic regression models. The role of PCO in the above associations was evaluated by mediation analyses. After adjusting for covariates, each 2-fold increase in serum bifenthrin was associated with a 0.21 mmol/L increase in FPG and a 5.19%, 10.49%, and 12.18% increase in FPI, HOMA-IR, and PCO levels, respectively. Monotonically elevated ORs of IFG and AGR (all P and P for trend <0.05), but not T2DM (P > 0.05) were detected to be associated with increased bifenthrin. Compared with the participants with low bifenthrin and low PCO, participants with high bifenthrin exposure and high PCO showed a 0.40 mmol/L, 11.07%, and 22.50% increase in FPG, FPI, and HOMA-IR, as well as a 119.97% and 48.88% increase in risks of IFG and AGR, respectively (P for trend <0.05). Moreover, PCO mediated 13.61%–24.98% of the serum bifenthrin-associated glucose dyshomeostasis. The study suggested that bifenthrin exposure was dose-dependently associated with glucose dyshomeostasis in the general Chinese urban adults, and these associations were exacerbated and partly mediated by PCO. Given that other pollutants were not included in this study, the effect of co-exposure of pyrethroids with multiple pollutants is necessary to be considered in future studies. [Display omitted] • Serum bifenthrin was dose-dependently associated with glucose dyshomeostasis. • Protein carbonylation exacerbated bifenthrin-associated glucose dyshomeostasis. • Protein carbonylation partly mediated bifenthrin-associated glucose dyshomeostasis. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • A U-shaped relationship was observed between ΣOHPh and FPG. • AMER3 variants modify the U-shaped relationship between ΣOHPh and FPG. • The role of AMER3 in glucose metabolism warrants further investigation. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) exposure has been related to the abnormal glucose metabolism and the risk of diabetes. However, the joint effects of various PCBs are uncertain and the potential mechanisms remain unclear. Our objectives were to evaluate the associations of serum PCBs with fasting plasma glucose (FPG) and the risk of diabetes among a general Chinese population, and to estimate the mediating effects of oxidative stress in the above associations. Serum levels of seven indicator-PCBs (PCB-28, 52, 101, 118, 138, 153, and 180) and FPG values were determined among 4498 subjects from the Wuhan-Zhuhai cohort. Oxidative DNA damage biomarker (urinary 8-hydroxy-2′-deoxyguanosine, 8-OHdG) and lipid peroxidation biomarker (urinary 8-isoprostane, 8-iso-PGF 2α) were also measured. Positive relationships of serum PCBs with FPG values as well as the risk of diabetes were observed. With each 1% increment in the natural log-transformed values of wet weight serum PCBs, FPG levels increased a 0.125% for PCB-52, 0.168% for PCB-118, 0.221% for PCB-138, 0.273% for PCB-153, and 0.379% for ΣPCB (the sum of seven PCBs). The adjusted odds ratios of diabetes associated with wet weight PCBs were 1.186 for PCB-52, 1.373 for PCB-118, 1.635 for PCB-153, and 1.456 for ΣPCB. The seven serum PCBs showed positive overall effect on the risk of diabetes. Elevated PCB-28, PCB-52, PCB-118, PCB-138, PCB-153, and ΣPCB were associated with the increased urinary 8-iso-PGF 2α , which was positively related with FPG values. Furthermore, urinary 8-iso-PGF 2α partially mediated the positive associations between PCBs and FPG values, with the mediated proportions ranged from 3.20 to 12.93%. In conclusion, our results suggested that serum PCBs were positively related with increased oxidative stress, FPG values, and the risk of diabetes among a general Chinese population. Serum PCBs mixture had positive overall effect on the risk of diabetes. Lipid peroxidation partly mediated the FPG elevation induced by PCB exposure. [Display omitted] • Serum PCB-52, 118, 138, and 153 and ∑PCB were positively associated with FPG levels. • Serum PCB-52, 118, and 153 and ∑PCB were positively associated with risk of diabetes. • PCBs mixture showed positive overall effect on the risk of diabetes. • Increased serum PCBs were associated with elevated urinary 8-iso-PGF 2α. • Urinary 8-iso-PGF 2α mediated the associations between serum PCBs and increased FPG. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) have been reported to cause various health damages. However, some PAH derivatives are still used as agents, and some of them have hypoglycemic effects. Till now, few studies explored the relationship between urinary PAH metabolites and fasting plasma glucose (FPG). In this study, A total of 2682 non-smokers in the second follow-up of the Wuhan-Zhuhai cohort were included to explore the relationship between urinary PAH metabolites and FPG. FPG related epigenome-wide association study (EWAS) was conducted among 212 never smokers, and the mediation analysis was performed to find potential mediator cytosine-phosphoguanine (CpG) sites in the above relationship. The concentration of total urinary PAH metabolites was 3.60 (2.37, 5.85) μg/mmol Cr. The urinary PAH metabolites were negatively associated with FPG. Each 1-U increase in ln-transformed levels of 1-hydroxynaphthalene, 4-hydroxyphenanthrene, 9-hydroxyphenanthrene, or 2- hydroxyphenanthrene was associated with 0.008-, 0.007-, 0.010-, or 0.010- unit decreased in ln-transformed levels of FPG, respectively (all p < 0.05). We found 28 new CpG sites related to FPG (FDR <0.05) through EWAS. Mediation analysis found that cg11350141 on AMER3 mediated 41.91% of the negative association of total urinary PAH metabolites with FPG. These results provide a new clue for the development of hypoglycemic agents. [Display omitted] • This is the first study that found low doses of urinary PAH metabolites were negatively associated with FPG. • The cg11350141 in the AMER3 gene mediated the PAH-associated FPG reduction. • We have newly discovered 28 CpG sites related to FPG. [ABSTRACT FROM AUTHOR]