| Objective:1.To explore the associations of prenatal PAHs exposure with neurodevelopment and physical growth among children aged 0-2 years.2.To evaluate the feasibility of 5-hmC of neurodevelopmental genes MeCP2 and BDNF as molecular markers in the process of neurodevelopmental disorders in children aged 0-2 years induced by prenatal PAHs exposure.Methods:A total of 400 mother-newborn pairs were recruited from cooperative hospitals in Taiyuan.After obtained by informed consent from participants,we applied the questionnaire to collect basic information about mother-newborn.When the infants were three days old,NBNA scale was applied to assess neonatal neurobehavioral development.After two years,we conducted the follow-up and evaluated neurodevelopment and physical growth among children aged 2 years.The Gesell neurodevelopment scale was used to measure neurodevelopmental indexes of 2-year-old children.The 11 OH-PAHs levels in pregnant women urine samples were analyzed using high performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).We used the high performance liquid chromatography(HPLC)to measure the BPDE level in cord blood leukocyte.The MeCP2 and BDNF gene 5-hmC level were analyzed using co-immunoprecipitation combined with real time PCR.General linear model,mixed linear model,and multiple linear regression models were used to investigate the association of prenatal PAH exposure(OH-PAHs and BPDE)with neurodevelopment and physical growth and 5-hmC level of MeCP2 and BDNF gene.Furthermore,the mediation analysis was conducted to investigate whether 5-hmC of MeCP2 and BDNF genes can serve as a mediator between PAHs exposure and 0~2-year-old children's neurodevelopment.Results:1.The mother-newborn pairs basic information and prenatal PAHs exposure levelsThe rate of lost to follow-up was 44.8%.There were no significant differences for basic information between original cohort and follow-up cohort,except for pregnant women education status.Compared with original cohort,the participants included into the follow-up cohort had higher education status(56.6%vs.46.2%).The detection rate of3-OHChr,6-OHChr,and 9-OHBap in pregnant women urine were less than 50%.The median of 2-OHNap is 3.26?g/L,which is highest PAHs metabolites in 11 OH-PAHs.The median and interquartile range of BPDE were 5.40*10~8/nucleotide and(3.50,8.40)*10~8/nucleotide,respectively.2.Neurodevelopment and physical growth in offspringThe means of birth weight,length,head circumference,and NBNA scores in newborns were 3467.3 g,50.7 cm,33.9 cm,and 38.6 scores,respectively.The average of physical development indexes in 2-year-old children(height,weight,and head circumference)were 87.3 cm,13.0 kg,and 47.9 cm,respectively.The four items average scores of the Gesell neurodevelopment scale were 111.6,110.5,108.8,and 111.7,respectively.A univariate analysis result showed there were statistical significant difference among low,middle,and high exposure group with birth weight and four items scores from Gesell neurodevelopment scale(P<0.05).3.Prenatal exposure to PAHs,neurodevelopment,and physical growthMaternal urinary 1-OHPyr and?-OHPAHs were inversely associated with newborn birth weight(P<0.05.Each 10-fold increase in 1-OHPyr and?-OHPAHs,the newborn birth weight averagely decreased by 152.49 g and 206.52 g,when others variables had no change.The 1-OHPyr in pregnant women urine was inversely correlated with neonatal NBNA scores.As the level of 1-OHPyr increasing,the neonatal NBNA score showed a downward trend(P=0.008).Maternal urinary 1-OHPyr,?-OHPAHs and cord blood leukocyte BPDE were negatively correlated with the Gesell neurodevelopmental score in2-year-old children.With the increase of 1-OHPyr,?-OHPAHs and BPDE levels,the 4items of Gesell neurodevelopmental scale scores showed a downward trend,and the test for trend had statistically significant.4.Association between prenatal PAHs exposure and the 5-hmC levels of MeCP2 and BDNF gene promoter in cord bloodUnivariate analysis indicated that the 5-hmC levels of the MeCP2 and BDNF gene promoters had a statistically different in the low,middle and high exposure groups(P<0.05).With the levels of 1-OHPyr and?-OHPAHs in the pregnant women urine increasing,the 5-hmC levels of MeCP2 and BDNF genes showed a decline trend.The test for trend has a statistically significant(P<0.05).Multiple linear regression suggested that each 10-fold increasing in 1-OHPyr and?-OHPAHs levels,the 5-hmC level of MeCP2 decreased by 32.4%and 53.2%and the 5-hmC level of BDNF gene decreased by 38.3%and 45.0%,respectively(P<0.05).5.Association between 5-hmC levels of MeCP2 and BDNF genes and neurodevelopment in children aged 0-2 yearsMultiple linear regressions showed the 5-hmC levels of MeCP2 and BDNF gene promoters were related to multiple neurodevelopmental indicators of offspring.The5-hmC level of MeCP2 was positively correlated with the adaptive and language scores of 2-year-old children.Each 10-fold increase in the 5-hmC level of MeCP2 gene promoter,Gesell neurodevelopment scale score of the two-year-old children averagely increased 6.77 points and 7.19 points in adaptive and language ability aspects(P<0.05).The 5-hmC level of BDNF gene promoter was positively correlated with neonatal NBNA score and behavioral,adaptive and language ability scores at 2 years of age(P<0.05).6.Mediation effect analysisThe 5-hmC of BDNF gene promoter can serve as a mediated role in the association between maternal urinary PAH metabolites(1-OHPyr and?-OHPAHs)and 2-year-old children behavioral ability scores.The changes of 5-hmC level of BDNF gene can explain 19.95%and 13.79%of the total variation resulted from the effect of 1-OHPyr and?-OHPAHs on behavioral ability scores in 2-year-old children(P<0.05).Conclusions:1.Prenatal PAHs exposures have an adverse effect on neurodevelopment and physical growth of the offspring(0-2 years).2.The 5-hmC of the BDNF gene promoter can be used as a biomarker in the process of neurodevelopmental disorders in children aged 2-year-old induced by exposed to PAHs during pregnancy. |
PDF Full Text Request