| Background:Asthma and wheezing pose a serious threat to children’s health,but the overall control level of it in children in China is still not ideal.Numerous studies have shown that PM2.5 and PM10 exposure during pregnancy is associated with asthma or wheezing in children.However,few studies have assessed the relationship between the more toxic PM1 exposure during pregnancy and asthma or wheezing in children.In addition,the biological mechanism of asthma or wheezing in children caused by PM1 is not completely clear.Recent studies suggest that the methylation changes of iNOS,STAT6,and FOXP3 genes may be the potential mechanism of asthma or wheezing caused by PM1,but there is no direct epidemiological evidence.Objective:This study aimed to evaluate the effects of PM1 exposure during pregnancy and various stages of embryonic lung development(the embryonic,pseudoglandular,canalicular,saccular and alveolar stages)on asthma or wheezing in children,to determine the sensitive exposure windows,and to further analyze the role of altered methylation levels of neonatal iNOS,STAT6,and FOXP3 genes in asthma or wheezing induced by PM1 exposure during pregnancy.Method:All the subjects were recruited from a previous birth cohort conducted in Guangzhou.The spatiotemporal land-use-regression model(ST-LUR)was used to evaluate the exposure level of PM2.5 during pregnancy and each stage of embryonic lung development,and the generalized additive model(GAM)was used to evaluate the exposure level of PM1 combined with PM2.5 data.The diagnoses of asthma or wheezing were extracted from children’s medical records.Cox proportional hazards models were used to evaluate the association between PM1 exposure during pregnancy and different stages of embryonic lung development and children asthma or wheezing,and to clarify the sensitive exposure window.Based on the aforementioned birth cohort,the nested case-control studies was established.The Pyrosequencing and MassARRAY were used to detect the methylation levels of iNOS,STAT6,and FOXP3 genes in the umbilical cord blood of newborns.The generalized linear model was used to explore the relationship between PM1 exposure during pregnancy and methylation levels of the above three genes,and the logistic regression model was used to analyze the relationship between methylation levels of these three genes and asthma or wheezing in children.Result:A total of 3725 pairs of pregnant women-children were included,and the incidence of asthma or wheezing in children was 10.52%(n=392).The average PM1 concentration during pregnancy(4.55 μg/m3 per IQR increment)was positively correlated with the risk of asthma or wheezing in children,with an adjusted hazard ratio(HR)of 1.39(95%CI:1.02,1.90).Subgroup analysis showed that the risk of exposure to PM1 was higher(HR=1.57,95%CI:1.02,2.41)in the pseudoglandular period(IQR=8.11 μg/m3).In addition,PM1 during pregnancy was negatively correlated with neonatal iNOS(IQR=4.44 μg/m3,β=-1.19%,95%CI:-2.23%,-0.15%)and FOXP3(IQR=4.54 μg/m3,β=-1.38%,95%CI:-2.75%,-0.02%),and neonatal iNOS(IQR=5.6%5mC,OR=0.62,95%CI:0.43,0.88),FOXP3(IQR=7.56%5mC,OR=0.87,95%CI:0.64,1.19)methylation were also all negatively correlated with children asthma or wheezing.And the neonatal STAT6 methylation was negatively associated with PM1 during pregnancy(IQR=3.87 μg/m3,β=-0.97%,95%CI:-2.08%,0.14%)and positively associated with asthma or wheezing in children(IQR=4.92%5mC,OR=1.35,95%CI:0.94,1.96).Conclusion:Maternal PM1 exposure during pregnancy may increase the risk of asthma or wheezing in children,and the pseudoglandular period may be the sensitive exposure windows.In addition,the decreased methylation level of the iNOS gene in newborns may be the potential methylation mechanism of asthma or wheezing in children caused by PM1 exposure during pregnancy,while the role of FOXP3 and STAT6 gene methylation needs to be confirmed by further studies.Therefore,pregnant women and their offspring should take early and effective measures to reduce PM1 exposure during pregnancy,especially in the sensitive exposure window. |
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