The Prospective Nested Case-Control Study Of The Association Between Persistent Organic Pollutants Exposure And Gestational Diabetes Risk

BackgroundGestatioan diabetes mellitus(GDM),a clinical manifestation of abnormal glycometabolism during pregnancy,is a significant public health issue that affects the maternal and child health.In recent years,the global prevalence of GDM increased rapidly while the traditional risk factors,e.g.,maternal age,obesity,family history of diabetes,fails to fully account for the high incidence of GDM.Environmental persistent organic pollutants(POPs)as toxic and hazardous substances exhibit potential endocrine disrupting effect at low body exposure level,which could disrupt insulin synthesis,secretion and signaling pathway,and ultimately result in insulin resistance,?cell function impairment and glycometabolism disorder.Hence,the environment factor could be the plausible contribution in the etiology of GDM.There is a special need to conduct the prospective analysis of the association between typical POPs,e.g.,dioxin-like compounds(DLCs),polychlorinated biphenyls(PCBs),polybrominated diphenyl ethers(PBDEs)and perfluoroalkyl acids(PFAAs)exposure and GDM risk.MethodsA prospective nested case-control study was conducted to investigate the association between typical POPs exposure and GDM risk.Healthy pregnant women without a previous history and a family history of diabetes were recruited at their initial prenatal care visit beween 2013 and 2015 at Xicheng Maternal&Child Health Hospital in Beijing.Pregnant women recruited in the cohort had provide first trimester blood samples for POPs exposure analysis.Participants were screened for GDM using a 75-g oral glucose tolerance test(OGTT)at 24-28 weeks of gestation.For each GDM subject,two healthy women without GDM were selected as pair-matched controls(birthdays within 2 years).The gas chromatography-high resolution mass spectrometry was used to measure the serum level of 29 DLCs,6 non-dioxin like PCBs and 7 PBDEs.The ultra-performance liquid chromatography tandem triple-quadrupole mass spectrometry was used to measure the serum level of 25 PFAAs.Conditional logistic and linear regression were used to evaluate the association between POPs exposure and both GDM risk and glucose levels,respectively.Weighted Quantile Sum(WQS)regression was used to estimate the mixed effect of all POPs exposure on GDM risk.LASSO regression was used to performs a variable selection in identification of important mixture componentsResults1.The association between DLCs exposure and GDMCombined exposure of PCDD/Fs and dl-PCBs calculated as total TEQ significantly increased the risk of GDM with an estimate odds ratio(OR)of 2.12(95%CI:1.57,2.86).The adjusted ORs(95%CIs)of GDM across total TEQ quartiles were Q1:1.00(ref.),Q2:2.04(0.78,5.35),Q3:4.02(1.61,10.06),Q4:7.74(3.10,19.29),p trend<0.001.The increment of total TEQ was also significant associated with increased fasting and postprandial glucose(p<0.05).The REPs of DLCs based on GDM and FBG were calculated from the ratios of regression coefficients,?_i(DLCs)/?TCDD.Two sets of consistent human serum-based REPs,i.e.,GDM-REP and FBG-REP,were established and largely agree with REPs from other human studies.These human-serum REPs show much smaller variation compared to the 4 to 5 orders of magnitude span in REPs database for the present WHO-TEF determination.Moreover,the established REPs fitted well with WHO-TEFs.2.The association between non-dioxin like PCBs exposure and GDMThe odds ratios(OR)of PCB-28,PCB-52,and PCB-101 for GDM were 1.86(95%CI:1.05-3.27),1.90(95%CI:1.28-2.82)and 1.85(95%CI:1.22-2.82),respectively.No statistical association was evident for other PCBs.However,after adjusting for confounders including some PCB congeners,only PCB-52 remained significantly associated with GDM with OR of 1.97(95%CI:1.27-3.07).Moreover,PCB-52 was positively associated with all blood glucose values of OGTT(P<0.05).3.The association between PBDEs exposure and GDMMedian concentrations of PBDEs were higher in women with GDM.Analyses parameterizing PBDE concentrations as continuous variables suggested significant associations between BDE-153,-154,-183 and GDM risk with an estimated odds ratio of 4.04(95%CI:1.92-8.52),1.88(95%CI:1.15-3.09)and 1.91(95%CI:1.31-2.08),respectively.In the quartile analyses,a significant increase in the odds ratio of GDM was associated with the highest levels of BDE-153(OR=3.42,95%CI:1.49-7.89)and BDE-183(OR=3.70,95%CI:1.58-8.65),whereas,BDE-154 demonstrated an inverted U-shaped association with GDM.In addition,BDE-153 and-154 were significantly positively associated with fasting glucose,and both 1 h and 2 h glucose level(P<0.05).4.The association between PFAAs exposure and GDMAmong the 25 PFAAs,12 perfluoroalkyl carboxylates(PFCAs)and 8perfluoroalkyl sulfonates(PFSAs)were detected in>55.0%of samples and were respectively grouped into different structural groups.The structural-based effect was observed for PFCAs,where short-chain(C4-C7)PFCAs continuous level was significantly associated with GDM with an OR of 1.99(95%CI:1.29-3.09),and the multivariable-adjusted ORs(95%CI)of GDM for increasing tertiles of short-chain PFCAs were 1.00(ref.),1.82(0.80-4.16)and 3.01(1.31-6.94),P trend=0.011.Additionally,increased concentration of short-chain PFCAs was significantly associated with higher postprandial glucose levels(P<0.05).Non-significant association was observed between structure grouped PFSAs and GDM as well as glucose homeostasis.5.The mixed effects of POPs combined exposure and GDM riskThe exposure level of 35 POPs with detection rate>80.0%exhibited high internal correlation,except for short-chain PFCAs(PFBA,PFPeA and PFHxA).The mixed effect estimated from WQS regression indicated significant association between POPs combined exposure and GDM risk(P<0.01).In addition,this association exhibited obviously dose-response relationship.The increment of total TEQ was associated with significant increase of 1 h PBG level(P<0.01).DLCs were identified as the most important mixture components of 35 POPs.In addition,PCB-101 has a significant modification effect on the association between Total TEQ and GDM.ConclusionPOPs exposure in early pregnancy increase the risk of GDM and alter the glucose homeostasis.Dioxin like compounds are the most potent pollutants in relation to the GDM risk.These REPs calculated from human epidemiological study reflecting real human exposure scenarios exhibite validity and could be used to improve risk assessment of human body burden of DLCs.