| Heavy metal(loid)s and phthalates acid esters(PAEs)are the most two classes of common environmental pollutants,some of which have been confirmed to act as endocrine disrupting chemicals.On the basis of an ongoing birth cohort in Wuhan,the toxic heavy metal(loid)s(hereinafter referred to heavy metals)and PAEs were selected in this study.We aimed to investigate the levels and determinants of exposure to abovementioned environmental pollutants during pregnancy.This study was also conducted to investigate the relationships of heavy metals and PAEs with infant growth patterns,and explore the potential mediating role of mtDNAcn in the associations between environmental pollutants and growth patterns.Part Ⅰ Maternal exposure to heavy metals and phthalates:concentrations and determinants of exposureObjective:To investigate the exposure levels and determinants of heavy metals and phthalates during the three trimesters.Methods:A total of 762 pregnant women were recruited in Wuhan Children’s Hospital from November 2013 to March 2015.The concentrations of urinary heavy metals(e.g.,As,Cd,Tl,Pb,and Cr)were measured using inductively coupled plasma mass spectrometry,and ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry was used to measure the urinary concentrations of six phthalate metabolites including MEP,MECPP,MEHHP,MEOHP,MNBP,and MEHP.Multivariable linear regression models were performed to identify potential determinants of the exposure levels of heavy metals and PAEs.Result:The detection rates of heavy metals ranged from 98.8%to 100%,and the detection rates of phthalate metabolites ranged from 84.5%to 99.9%.The urinary concentration of As was the highest in heavy metals,and the median concentrations in the first,second,and third trimester were 16.853 μg/L,16.086 μg/L,and 17.150 μg/L,respectively;the urinary concentration of MNBP was the highest in phthalate metabolites,and the median concentrations in the three trimesters were 45.276 μg/L,40.725 μg/L,and 68.054 μg/L,respectively.Maternal age was significantly associated with increased urinary Cd concentrations in the first,second,and third trimesters(P<0.05).The significant association between pre-pregnancy BMI and urinary T1 concentrations was observed in the second trimester(P<0.05).Maternal multivitamin supplementation significantly associated with lower urinary concentrations of MECPP,MEHHP,and MEOHP during the second trimester of pregnancy(P<0.05).Conclusions:Prenatal exposure to heavy metals and PAEs was highly prevalent in the present study population.Multiple factors including maternal age,pre-pregnancy BMI,and nutrients supplementation might be critical determinants for the urinary concentrations of heavy metals and PAEs during pregnancy.Part Ⅱ Associations of prenatal exposure to heavy metals and phthalates with newborn mitochondrial DNA copy numberObjective:To investigate the associations of exposure to heavy metals and phthalates during the three trimesters of pregnancy with newborn mitochondrial DNA copy number.Methods:Based on the participants in Part I,cord blood mtDNAcn was determined using qPCR.Multiple informant models were used to examine the associations of prenatal exposure to heavy metals and phthalate metabolites with cord blood mtDNAcn.Bayesian kernel machine regression(BKMR)was used to estimate the joint effect of heavy metals and phthalates on newborn mtDNAcn.Result:In the multivariable-adjusted models,each doubling increase in urinary As,Tl,and Cd levels at the first trimester was associated with 7.39%(95%Cl:-12.76%,-1.69%),10.37%(-16.43%,-3.87%),and 7.10%(-12.35%,-1.54%)decreased mtDNAcn,respectively.In addition,each doubling increase in the first trimester urinary MEOHP level was associated with 4.27%(-8.03%,-0.36%)decreased mtDNAcn.In BKMR models,we observed a significant linear dose-response relationship between maternal exposure to pollutants mixture during the first trimester and mtDNAcn,whereas the associations were insignificant for the second and the third trimester.Conclusions:Prenatal exposure to As,Tl,Cd,and MEOHP during the first trimester was related to decreased cord blood mtDNAcn,and the first trimester might be a critical window for susceptibility to heavy metal or phthalates exposure.Part Ⅲ The associations of prenatal exposure to heavy metals and phthalates with infant growth patterns and the mediating role of newborn mitochondrial DNA copy numberObjective:To study the associations of prenatal exposure to heavy metals and phthalates with infant growth patterns and the mediating role of newborn mitochondrial DNA copy number in these associations.Methods:Based the participants in Part Ⅱ,the newborns were followed up to obtain their weight and length at ages 0,1,3,6,8,12,18,and 24 months.Superimposition by translation and rotation growth curve analysis(SITAR)and latent class mixed model(LCMM)were performed to fit individual growth curves and group-based growth trajectories,respectively,and therefore to evaluate the growth patterns in infants.Multiple informant models were used to examine the associations of exposure to heavy metals and phthalates with growth parameters,and multinomial logistic regression analyses were used to estimate the associations of maternal exposure to heavy metals and phthalates with growth trajectories.We also performed mediation analysis to explore the mediating role of newborn mtDNAcn on the associations of prenatal exposure to heavy metals and phthalates with infant growth patterns.Result:(1)The individual-specific parameters of growth curves were generated by fitting individual growth curves of length,weight,and BMI by SITAR.After adjustment for potential covariates,the growth size of length growth curves in females decreased by 0.426(95%Cl:-0.827,-0.025),0.418(-0.816,-0.020),and 0.319(-0.560,-0.078)for each lg-unit increase in MEHHP during the first trimester,MEOHP during the first trimester,and MNBP during the third trimester,respectively.Each lg-unit increase in MEHHP,MEOHP,and MEHP exposure during the second trimester,the growth intensity of BMI growth curves increased by 0.476(0.065,0.886),0.548(0.132,0.965),and 0.294(0.021,0.568)in females,respectively.Maternal exposure to Cr during the second trimester was significantly associated with increased length growth size(β:0.467;95%CI:0.071,0.864)in males.In addition,the mediation analysis suggested that newborn mtDNAcn had significant suppression effect on the relationships of urinary MECPP and MEOHP exposure during the first trimester with decreased length growth size.(2)The growth trajectories of length,weight,and BMI were fitted by LCMM.After adjustment for potential covariates,prenatal exposure to MECPP(OR:3.30;95%CI:1.08,10.10),MEHHP(OR:3.48;95%CI:1.21,10.05),and MEOHP(OR:3.67;95%CI:1.28,10.55)during the first trimester was associated with higher odds of slow growth trajectory of length in females.Maternal exposure to Cr(OR:2.10;95%CI:1.22,3.62)during the second trimester was associated with increased odds of slow growth trajectory of length in males.Prenatal exposure to T1(OR:4.49;95%CI:1.18,17.08)during the second trimester was associated with greater odds for fast growth trajectory of BMI in males.In addition,the mediation analysis suggested that the associations of urinary MECPP and MEOHP concentrations in the first trimester with the slow growth trajectory of length were suppressed by newborn mtDNAcn.Conclusions:Prenatal exposure to heavy metals and phthalates has significant adverse effects on the parameters of growth curves and infant growth trajectories.The increased neonatal mtDNAcn may suppress a part of the adverse effect of prenatal exposure to phthalates during the first trimester on the growth size and slow growth trajectory of length in females. |
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