Associations Of Urinary Propylene Oxide Metabolites With Fasting Plasma Glucose And Type 2 Diabetes Mellitus And Potential Role Of Oxidative Stress Assessment In Community-based Population

Propylene oxide（PO）is a colorless,ether-scented volatile organic compound which is widely used in modern chemical production and environmental disinfection.General population can be exposed to PO via cigarettes,foods and medical equipment disinfection residues.PO is metabolized into N-Acetyl-S-（2-hydroxypropyl）-L-cysteine（2HPMA）by glutathione S-transferase and epoxide hydrolase,and eventually excreted with urine.2HPMA is considered to be a reliable biomarker for PO exposure.In recent years,the health damage of PO exposure,such as carcinogenicity and respiratory system damage,has been studied extensively.PO exposure may also lead to dysglycemia,but research is insufficient and the mechanism is unclear.Previous studies have confirmed that the increase of oxidative stress level induced by PO exposure play an important role in its health damage effect.In addition,oxidative damage has been confirmed to cause insulin resistance,pancreatic beta cell damage.Therefore,this study hypothesized that PO exposure may lead to dysglycemia by inducing oxidative damage.This study was based on the Wuhan-Zhuhai cohort established earlier.Urinary PO metabolite and biomarkers of oxidative stress（DNA oxidative damage and lipid peroxidation）were measured among the cohort baseline population to assess PO exposure and oxidative stress level.The association of PO exposure with blood glucose and risk of type 2 diabetes mellitus（T2DM）,as well as the roles of DNA oxidative damage and lipid peroxidation were explored.The epidemiological investigation and biomarkers determination of this study were guaranteed by a quality control system,and the study was approved by the ethics committee of the medical college.Part I.Associations of urinary propylene oxide metabolite with fasting plasma glucose and type 2 diabetes mellitusObjectives:To assess PO exposure in community population and evaluate the association of PO exposure with blood glucose and risk of T2DM.Methods:Baseline population of the Wuhan-Zhuhai cohort established earlier was taken as the study population.After excluding participants without data and sufficient biological samples and with kidney diseases,a total of 3294 community residents were included in the study.All participants signed informed consent.In this cross-sectional study,Information of participants were collected through a face-to-face interview.Height,weight and other anthropometric indicators were obtained through physical examination.Fasting blood samples and morning urine were collected.Fasting plasma glucose（FPG）and urinary creatinine（Cr）were measured using an automatic biochemical analyzer.Urinary 2HPMA of 3294 participants were measured via an ultra-high performance liquid chromatography system coupled with electro spray tandem mass spectrometry.Urinary creatinine was used to calibrate for 2HPMA concentrations.Before the regression analysis,the non-normally distributed data were converted logarithmically to improve its normality.The 2HPMA concentration was taken as a continuous variable or as a categorical variable according to its quartiles.Generalized linear model and logistical regression model were constructed to assess the association of 2HPMA with FPG and risk of T2DM,respectively.Stratified analyses and modification analyses were performed according to basic characteristics.Results:1.The average age of 3294 community population included in this study was 53.02years old.Participants included 983 males（29.84%）,487 smokers（14.78%）,419drinkers（12.72%）,and 1609 participants（48.85%）who did physical exercise regularly.The average level of FPG was 4.85 mmol/L,and there were 283（8.59%）diabetic patients.The median urinary 2HPMA concentration was 2.02（25%-75%,1.24-3.41）μg/mmol of Cr.Subgroups of≥50 years old（2.70μg/mmol Cr）and smokers（3.58μg/mmol Cr）had significantly higher urinary 2HPMA geometric mean concentrations than subgroups of<50 years old（2.56μg/mmol Cr）and nonsmokers（1.93μg/mmol Cr）after adjusting for confounders,respectively（all P<0.05）.2.Significant positive association was found between 2HPMA and FPG in both the continuous model and the categorical model after adjusting for potential confounding factors,and each 1-unit increase in log-transformed concentration of urinary 2HPMA was associated with a 0.15-mmol/L increase in FPG levels（P<0.05）.Compared with the first quartile,FPG levels showed a dose-response elevation across 2HPMA quartiles(P _trend<0.05).Significant positive association was found between 2HPMA and the risk of T2DM in both the continuous model and the categorical model after adjusting for potential confounding factors(P<0.05,P _trend<0.05).In continuous variable model,the OR value with 95%confidence interval（CI）were 1.47（95%CI:1.03,2.11）.3.The association of 2HPMA with FPG and risk of T2DM was not signifcantlly modificated by any grouping factors(P _modification>0.05).Stratified analysis found a significant association between urinary 2HPMA concentration and FPG in subgroups of age<55,men,BMI<24,nonsmokers,did physically active infrequently,or nondrinkers（P<0.05）.However,the association between 2HPMA and risk of T2DM was only found in subgroup of did physically active infrequently（P<0.05）.Conclusion:The PO exposure level of elderly persons（age≥55）and smokers were higher than younger persons（age<55）and nonsmokers.There were dose-response relationships of PO exposure with FPG and the risk of T2DM,respectively.Part II.The role of oxidative stress in the association of urinary propylene oxide metabolite with fasting plasma glucose and type 2 diabetes mellitusObjectives:To evaluate the association of PO exposure with DNA oxidative damage and lipid peroxidation,and analyze the roles of the two kinds of oxidative stress biomarkers in the association between PO and hyperglycemia.Methods:On the basis of part I,urinary 8-oxo-7,8-dihydro-20-deoxyguanosine（8-OHdG,biomarker of DNA oxidative damage）concentrations were detected by a high performance liquid chromatography coupled with an electrochemical detector,and urinary 8-iso-Prostaglandin F2α（8-iso-PGF2α,biomarker of lipid peroxidation）concentrations were measured by an enzyme-linked immunosorbent assay kit.Generalized linear model was used to assess the association of 2HPMA with the two kinds of markers of oxidative stress.Generalized linear model and restricted cubic spline model were used to assess the associations of the two kinds of markers of oxidative stress and FPG.Logistics regression model and restricted cubic spline model were used to assess the associations of the two biomarkers of oxidative stress and risk of T2DM.In order to construct interaction model,participants were divided into four groups according to the median concentration of urine 2HPMA and8-OHdG/8-iso-PGF2α,respectively.When the outcome was FPG,the interaction terms of 2HPMA concentration group and 8-OHdG/8-iso-PGF2αconcentration group were added into the model to analyze the additive interaction effect.When the outcome was T2DM,the relative excess risk due to interaction（RERI）was calculated.In addition,mediating effect models were constructed to evaluate the mediation role of 8-iso-PGF2αin the association between 2HPMA and FPG.Results:1.After adjusting for confounding factors,significant positive dose-response relationships of 2HPMA with 8-OHdG and 8-iso-PGF2αwere observed,respectively（P<0.05）.8-OHdG and 8-iso-PGF2αlevels were increased by 0.20%and 0.38%for each1%increase in log-transformed 2HPMA levels,respectively.A significant dose-response relationship between 8-iso-PGF2αand FPG was found（P<0.05）.2.When conducted stratified analyses according to 8-OHdG/8-iso-PGF2αconcentrations,significant modification effect of 8-OHdG on association between2HPMA and risk of T2DM was observed(P _modification<0.05).No significant increase in FPG levels was found compared with group with low2HPMA and low 8-OHdG concentrations,and the interaction effect was not statistically significant(P _interaction>0.05).But the risk of T2DM was significantly higher in all other groups compared with group with low 2HPMA and low 8-OHdG concentrations（P<0.05）,and the RERI suggested significant additive interaction effect exist（RERI=0.50,95%CI:0.30-0.85）.The results suggest that there is an additive interaction effect between urinary 2HPMA and 8-OHdG on the increased risk of T2DM.The group with high 2HPMA and high 8-iso-PGF2αconcentration had significant higher FPG levels compared with group with low 2HPMA and low 8-iso-PGF2αconcentrations（β=0.17,95%CI:0.04,0.30）,but no significant interaction effect was observed(P _interaction>0.05).The risk of T2DM in group with high 2HPMA and high8-iso-PGF2αconcentration was also significantly higher compared with groups with low 2HPMA and low 8-iso-PGF2αconcentrations（OR=1.49,95%CI:1.07,2.10）,and the RERI with its 95%CI were 1.34（0.79,2.30）.Urinary 2HPMA and 8-iso-PGF2αhave an additive interaction effect on the increased risk of T2DM.3.Mediation models found that 8-iso-PGF2αsignificantly mediated the 2HPMA inducted FPG level increase（P<0.05）,and the mediation proportion was 34.5%.Conclusion:PO exposure is significant positive associated with DNA oxidative damage and lipid peroxidation.Urinary 2HPMA and 8-OHdG or 8-iso-PGF2αhave an additive interaction on the increased risk of T2DM.Lipid peroxidation may partially mediate the association of PO exposure with hyperglycemia.