Association Of Urinary Metals And Circulating Fatty Acids With Risk Of Gestational Diabetes Mellitus

Gestational diabetes mellitus（GDM）is defined as glucose intolerance with onset or first recognition during pregnancy.As one of the most common pregnancy complications,GDM could lead to the serious health effects for pregnant women and their offspring.Data on prevalence of diabetes coming from International Diabetes Federation in 2019 shows that the incidence of GDM is gradually ascending in recent years.The occurrence of GDM is influenced by genes and environment.Recently,some researchers suggest that we should look for other potential risk factors to explain the occurrence and development of GDM.Increasing epidemiological studies found that endocrine-disrupting chemicals（EDCs）were associated with risk of GDM.Among these EDCs,the effect of endocrine disrupting metals including harmful and trace metals on human should not be neglected.Pregnant women are at a special physiological stage and are sensitive to harmful metals.At the same time,it is necessary to get adequate nutrients for pregnant women to meet the needs of fetal development.Trace metal elements mainly including zinc,manganese and chromium are one of the important nutrients.At present,several previous studies have reported the relationship between endocrine disrupting metals and risk of GDM,but the discrepant results were observed.The epidemiological evidence for the association of individual metals with risk of GDM is scant.In these studies,most researchers evaluated levels of metals by testing the samples in the second or third trimester.It could lead to the biased results,because most of GDM occurs in the second or third trimester,and the occurrence of GDM could change the metabolism of metals.It is necessary to collect biological samples in early pregnancy to detect the levels of metals,and further to explore their relationships with the risk of GDM.Based on the current evidence,we focused on the effects of five metals with strong endocrine disrupting effects including cadmium,chromium,manganese,arsenic and zinc on risk of GDM.An increasing number of studies showed that trace and harmful metals may interact with each other after entering the body.Considering the limited studies on metal interactions among pregnant women,it is necessary to further explore the role of interactions between harmful and trace metals on risk of GDM.In addition to trace metals,fatty acids also play an important role in maintaining maternal and fetal health during pregnancy.Many studies observed a possible association between fatty acids and the development of diabetes in the general population.However,there are few studies on associations between levels of fatty acids and risk of GDM in pregnant women,and the controversial results were shown based on the current evidence.With the in-depth understanding of saturated fatty acids,emerging evidence indicated that very long chain SFAs（VLSFAs）may be conducive to reducing the occurrence of metabolic disorders.For VLSFAs,epidemiologic evidence on their role in GDM is sparse.In recent years,researchers have questioned the health effects of fish oil,which is rich in n-3 polyunsaturated fatty acids.It is need to further explore the role of n-3 polyunsaturated fatty acids in the prevention of GDM.In our previous studies,we have repeatedly observed that cadmium exposure during pregnancy was associated with the risk of GDM.However,the biological mechanisms underlying the associations are unknown.A variety of animal studies have shown that cadmium exposure can cause disorders of fatty acid metabolism,but we didn’t find the evidence in population studies.Based on the existing evidence,it is necessary to further explore the potential role of fatty acids on the association between cadmium exposure and the risk of GDM.We conducted a nested case-control study based on a longitudinal cohort study to investigate the effects of metals and fatty acids on risk of GDM in pregnant women.In addition,we evaluated the relationship between cadmium exposure and levels of fatty acids in plasma,further explored the mediating effect of fatty acids on the association between cadmium and risk of GDM.Part 1:Association of urinary metals with the risk of gestational diabetes mellitusObjectives:To investigate the effects of endocrine disrupting metals on risk of GDM in pregnant women.Methods:A total of 305 GDM cases were matched to 305 controls on pregnant women’s age（±2 years）and infant’s gender from a birth cohort study conducted between October 2013 and October 2016 in Wuhan,China.Harmful metals including cadmium and arsenic and trace metals including chromium,manganese and zinc concentrations in urine between 10 and 16 gestational weeks were measured using inductively coupled plasma mass spectrometry.Conditional logistic regression models were used to calculate odds ratio（OR）and 95%confidence interval（95%CI）for associations of metals concentrations with the risk of GDM.For metals with significant association of GDM in multiple-metal models,we evaluated their joint associations and the non-linear relationship.The confounders for adjustment included age,education level,parity,pre-pregnancy BMI and passive smoking during pregnancy.In addition,we performed stratified analyses by maternal pre-pregnancy BMI and infant sex,and estimated p-values for interaction.Results:We observed the positive associations of GDM with cadmium in urine among all pregnant women.In contrast,higher levels of chromium and manganese in urine were associated with a lower risk of GDM.RCS showed the non-linear relationships of chromium and manganese with risk of GDM.When the analyses were stratified by infant sex,the significant associations of cadmium in urine with risk of GDM were observed among pregnant women with male infants.However,the interactions between these metals and infant sex were not observed.When the analyses were stratified by pre-pregnancy BMI,the associations of metals with risk of GDM among pregnant women with normal pre-pregnancy BMI were consistent with the associations among all the pregnant women.The negative associations of manganese with risk of GDM were found among overweight and obese pregnant women.In addition,we observed possible antagonistic interactions between harmful metal cadmium and trace metals including chromium and manganese on risk of GDM,and potential synergistic effects between chromium and manganese.Conclusions:Urinary cadmium,chromium and manganese concentrations were associated with risk of GDM in pregnant women.For the association of cadmium exposure with risk of GDM,the sex-specific differentials were found.There may be some antagonistic effects between harmful metals and trace metals on risk of GDM,while there may be some potential synergistic effects between trace metals.Part 2:Association of circulating fatty acids with the risk of gestational diabetes mellitusObjectives:To explore the associations between levels of circulating fatty acids in early pregnancy and risk of GDM in pregnant women.Methods:Levels of fatty acids in plasma were measured using gas chromatography-mass spectrometry among pregnant women coming from case-control study in Part 1.Due to the right-skewed distributions of fatty acids concentrations,natural logarithm transformations of fatty acids concentrations were performed to approximate a normal distribution for the following analyses.Conditional logistic regression models were used to calculate OR and 95%CI for associations of fatty acids with the risk of GDM.The levels of fatty acids were analyzed as categorical variables based on the tertile distributions among controls（the lowest tertile was defined as the referent group）.For fatty acids associated with the risk of GDM,we further evaluated the non-linear relationship between these fatty acids and the risk of GDM using RCS.The confounders for adjustment included age,education level,parity,pre-pregnancy BMI and passive smoking during pregnancy.Results:For saturated fatty acids（SFAs）,levels of myristic acid（14:0）,palmitic acid（16:0）,total long-chain SFAs（LSFAs）and total SFAs were positively associated with the risk of GDM.In contrast,higher levels of very long chain SFAs（VLSFAs）including arachidic acid（20:0）,behenic acid（22:0）,and lignoceric acid（24:0）were associated with a lower risk of GDM,and these relationships were non-linear.For odd-chain SFAs（OSFAs）including pentadecanoic acid（15:0）and heptadecanoic acid（17:0）,no significant difference was observed.For unsaturated fatty acids（UFAs）,levels of eicosapentaenoic acid（C20:5）,γ-linolenic acid（C18:3）,total monounsaturated fatty acids（MUFAs）and total n-3 polyunsaturated fatty acids（PUFAs）,and ratio of n-3 PUFAs and n-6 PUFAs were positively associated with the risk of GDM,while levels of linoleic acid（C18:2）,total n-6 PUFAs,total PUFAs and total UFAs were negatively associated with the risk of GDM.After false discovery rate（FDR）correction,C20:5 and total n-3 PUFAs were not statistically significant(P_FDR>0.05).Conclusions:Levels of fatty acids including LSFAs,VLSFAs,MUFAs and n-6PUFAs were associated with risk of GDM.For SFAs,different subclasses of SFAs showed diverse effects on the risk of GDM,and future studies are required to elucidate the underlying mechanisms.Part 3:Mediating effect of fatty acids on the association between cadmium and risk of gestational diabetes mellitusObjectives:To investigate the associations of urinary cadmium concentrations with levels of fatty acids in plasma,and further to examine the role of fatty acids in mediating the relationship between cadmium exposure and risk of GDM.Methods:Based on the Part 1 and 2,multiple linear regression models were applied to estimate the associations between cadmium concentrations and levels of fatty acids among normal pregnant women,and mediation analysis was used to assess the mediating role of fatty acids in the association of cadmium with the risk of GDM.Results:We observed significant negative associations of cadmium concentrations with levels of pentadecanoic acid（C15:0）,heptadecanoic acid（C17:0）,stearic acid（C18:0）,eicosapentaenoic acid（C20:5）,total odd-chain saturated fatty acids（OSFAs）and total n-3 polyunsaturated fatty acids（PUFAs）after adjusting for potential covariates（P<0.05）.For n-6 PUFAs,cadmium concentrations were positive associated with levels of eicosadienoic acid（C20:2）（P<0.05）.We did not observe evidence that the association of cadmium exposure and risk of GDM was mediated through fatty acids in early pregnancy.Conclusions:Cadmium exposure in early pregnancy could cause changes in the composition of fatty acids in plasma.Mediation effects of fatty acids in early pregnancy was not observed on the association between cadmium exposure and risk of GDM.