Association Of Trace Element Mixed Exposure During Pregnancy And Gestational Diabetes Mellitus

Gestational diabetes mellitus is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.It’s usually diagnosed during 24 to 28 weeks of pregnancy.GDM is a great public health concern,which affects 2~25% pregnant women worldwide.Adverse effects of GDM on maternal and fetal health are well demonstrated.Globally,GDM is associated with adverse perinatal and maternal outcomes such as macrocephaly,preeclampsia,cesarean section,neonatal hypoglycemia,premature delivery,and neonatal hyperbilirubinemia.In addition,there is evidence that adverse pregnancy outcomes may occur when blood glucose is under diagnostic criteria of GDM.The increasing prevelance of GDM and severe pregnancy outcomes require the identification of risk factors associated with GDM.The prevalence of GDM has increased over the past few decades.Lifestyle changes and environmental exposure may play a key role.Trace element is a common class of chemicals exposed during pregnancy,including both essential and probably essential trace elements obtained from foods and vitamin supplements,and potentially toxic trace elements exposed from groundwater,contaminated food,and vegetables.Some trace elements such as arsenic,cadmium,mercury,lead and selenium have certain endocrine disrupting effect,which can affect glucose metabolism and increase the risk of diabetes and cardiovascular diseases.However,previous studies have not drawn a consistent conclusion on the relationship between trace elements exposure and GDM.In addition,most previous studies only focused on the influence of single trace element on GDM,and rare studies treated trace elements as a mixture and explored the overall effect of multiple trace elements on GDM.In this study,the effects of trace element exposure during pregnancy on GDM were investigated through three steps.Firstly,we meta-analyzed the association between representative potentially toxic trace elements and GDM.By summarizing previous results,we obtained clues about the association of single potentially toxic trace element exposure with GDM.Secondly,the trace elements exposed during prengnancy are various,including potentially toxic trace elements,essential trace elements and probably essential trace elements.These trace elements are exposed at the same time.The single trace element analysis is not consistent with the actual exposure characteristics and mixed exposure could more accurately reflect the potential risk of trace element exposure during pregnancy.Before analysis,we firstly conducted statistical model comparison using NHANES data to assess their application in health assessment of mixed exposure and compare their advantages and disadvantages.We proposed a strategy for analyzing the health effects of chemical mixture exposure and it provided guidance for the association analysis between the mixed exposure of trace elements and GDM.Finally,after fully exploring the characteristics of each model,we investigated the overall effect of mixed exposure of trace elements on GDM in a prospective cohort study.In this study,we also identified GDM-related key trace elements,fitted their potential nonlinear dose-response relationship with GDM,and analyzed the relationships between trace elements.This study will provide clues for early prevention and intervention of GDM.Part Ⅰ Meta analysis of potentially toxic trace elements and gestational diabetes mellitusObjective The prevalence of gestational diabetes is gradually increasing,which is an important public health concern.More epidemiological studies have shown that potentially toxic trace elements including arsenic,cadmium,mercury and lead have certain endocrine disrupting effects and are correlated with gestational diabetes mellitus.However,previous results are inconsistent.This study systematically reviewed relevant literature by means of meta-analysis to provide complementary data for prevention decisions.Methods Electranic databases including Pubmed,Web of Science and Embase were searched for literatures on association analysis of exposure to four trace elements(arsenic,cadmium,mercury,and lead)and GDM based on keywords.After screening,evaluation and heterogeneity test,the combined effect was calculated using random effect model.The subgroup analysis was carried out according to the sample types and sampling time points.Results After screening,a total of 12 studies of high quality were included in the final analysis.The effects of four potential toxic trace elements(arsenic,cadmium,mercury,and lead)exposure on GDM were combined.The results indicated that comparing the top with the bottom thirds of baseline exposure levels,arsenic,cadmium and mercury exposure were significantly associated with GDM.The ORs and 95% confidence intervals were 1.80(1.16,2.80),1.45(1.02,2.06),and 1.31(1.07,1.59),respectively.There was no statistical association between lead exposure and GDM.Subgroup analysis of sample types revealed a significant association between urine cadmium exposure and GDM.Subgroup analysis based on sampling time points found that arsenic and cadmium exposure in the first trimester was significantly correlated with GDM,while other time points showed no statistical association.Conclusion Exposure to arsenic,cadmium and mercury is significantly correlated with GDM,and the first trimester may be the critical period for arsenic and cadmium exposure to induce GDM.Since pregnant women are exposed to multiple trace elements simutaniously,we need to explore the relationship between trace element mixed exposure and GDM in the following analysis.Part Ⅱ Explore the application of models in assessing healthy effect of mixed exposure in environmental epidemiology studyObjective Trace element exposure during pregnancy is characterized by mixed exposure to multiple elements,while previous studies are usually limited to analyzing the effects of exposure to a single trace element,and rarely analyze the impact of trace element mixture.In this study,we examined the applicability of three statistical models to assess the association between exposure to a mixture of xenobiotics and health outcomes,and compared the advantages and disadvantages of the three models and propse an analysis strategy for the following analysis of mixed trace element exposure during pregnancy and GDM.Methods As an example of the application,we analyzed the association between a mixture of seven exogenous chemicals(three phthalate metabolites,two phenols,and two pesticides)and obesity.The study was based on data from the National Health and Nutrition Examination Survey(NHANES)from 2013 to 2014.Exposure levels of environmental phenols,pesticides,and phthalate metabolites in the urine of participating adults were measured,and physical indicators were measured to determine obesity.We fitted a variety of models,including generalized linear regression(in this case multiple logistic regression and linear regression),weighted quantile sum(WQS)regression and Bayesian kernel machine regression(BKMR)model,to assess the association between chemical mixture exposure and obesity.Results Of 1269 individuals included in our final analysis,38.5% had general obesity and 57.8% had abdominal obesity.In the logistic regression model established for each single chemical,bisphenol S(BPS),mono(carboxyoctyl)phthalate(MCOP),and mono(2-ethyl-5-carboxypentyl)phthalate(MECPP)were associated with both general and abdominal obesity(fourth vs.first quartile).In linear regression,MCOP was associated with BMI and waist circumference.In WQS regression analysis,the WQS index was significantly associated with both general obesity(OR = 1.63,95% CI: 1.21–2.20)and abdominal obesity(OR = 1.66,95% CI: 1.18–2.34).MCOP,bisphenol A(BPA),bisphenol S(BPS),and mono ethyl phthalate(MEP)were the most heavily weighing chemicals.In BKMR analysis,the overall effect of mixture was significantly associated with general obesity when all the chemicals were at their 60 th percentile or above it,compared to all of them at their 50 th percentile.MCOP,BPA,and BPS showed positive trends.By contrast,MECPP showed a flat and modest inverse trend.No significant interaction was found between either of these chemicals.Conclusion When comparing results from these three models,MCOP,BPA,and BPS were identified as the most important factors associated with obesity.We recommend estimating the joint effects of chemical mixtures by applying multiple statistical methods and interpreting their results together,considering their advantages and disadvantages.We suggest that generalized linear regression,WQS and BKMR models should be used jointly to evaluate the effect of mixed trace element exposure during pregnancy on GDM.Part Ⅲ Association of urinary trace element mixed exposure in the first trimester and gestational diabetes mellitusObjective Trace element are widely exposed during pregnancy.Previous studies are limited to analysing the relationship between single trace element and GDM,while few studies focuse the effects of multiple trace element exposure on GDM.In this study,we investigated the relationship between mixed urinary trace elements exposure during the first trimester and GDM.Methods A prospective cohort study was conducted.We collected urine samples from pregnant women in the first trimester for trace element detection by inductively coupled plasma mass spectrometry(ICP-MS).Oral glucose tolerance test(OGTT)was performed at 24 to 28 weeks of gestation for GDM diagnosis.The generalized linear regression model,WQS and BKMR model were jointly conducted to investigate the association between trace element exposure and GDM according to the suggestions summarized in Part Ⅱ.Results Finally,902 participants were included in the analysis.15.4% were diagnosed with GDM in the second trimester.Compared with the first quartile level,the highest quartile exposure levels of arsenic and molybdenum were significantly associated with GDM(OR=1.90,95%CI: 1.07,3.38;OR=1.86,95%CI: 1.04,3.32,respectively).The highest quartile level of cobalt had a marginal negative association with GDM(OR=0.57,95%CI: 0.32,1.01).In the WQS analysis,we found that there was a significant positive association between the WQS index and GDM(OR=1.37,95%CI: 1.07-1.77),and arsenic and molybdenum had the largest weights.There was no significant negative association between the WQS index and GDM.In the BKMR analysis,the overall risk of GDM increased with the increasing of all trace element exposure levels.Among them,arsenic,molybdenum and cobalt had larger posterior inclusion probabilities,which indicates that they have a great contribution to the overall effect.We also found that when all the other trace elements were fixed at the median exposure level,arsenic and molybdenum showed an increased exposure-response relationship with GDM,while cobalt showed a decreased exposure-response relationship.We found no interaction between the GDM-related key trace elements.Conclusion Combined with the results of the three models,from the perspective of mixed exposure analysis,arsenic and molybdenum are risk factors for GDM,and cobalt exposure has a certain protective effect on GDM.Further research is needed to validate this result and to explore the involved mechanisms to facilitate early identification and intervention of GDM-related risk factors.