Associations Of Prenatal Exposure To Perchlorate,Thiocyanate,and Nitrate With Child Neurocognitive Development At 2 Years Old

Perchlorate,thiocyanate and nitrate are widely existed in various environmental media due to industry and daily usage,and have led to widespread human exposure.Previous animal studies suggest that perchlorate,thiocyanate,and nitrate exposure during pregnancy may affect children neurocognitive development possibly by interfering with thyroid hormones and inducing oxidative stress.But few epidemiological studies explored these associations.In China,there are very limited data on exposure profiles of perchlorate,thiocyanate,and nitrate among pregnant women.Therfore,this study was conducted to explore the exposure level of perchlorate,thiocyanate,and nitrate among Chinese pregnant women and to explore their potential health effect of pregnant women and their children.Part 1: Exposure profiles and predictors of urinary concentrations of perchlorate,thiocyanate,and nitrate among Chinese pregnant womenObjective: To reveal the exposure profile and predictors of perchlorate,thiocyanate,and nitrate concentrations during pregnancy among pregnant women in Wuhan,China.Method: Based on a prospective birth cohort study in Wuhan,China,1028 pairs were recruited from 2014 to 2017 with mothers provided urine samples across trimester and children evaluated neurocognitive development at 2 years old.Urinary concentrations of perchlorate,thiocyanate,and nitrate were measured using ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS).Spearman correlation coefficients of the three chemicals were calculated.Linear mixed-effects models were used to estimate intraclass correlation coefficients(ICCs)of perchlorate,thiocyanate,and nitrate during pregnancy and to explore the potential confounders.Result: Urinary perchlorate,thiocyanate,and nitrate were detected in 100% of the samples.The median specific gravity(SG)-adjusted concentration for perchlorate,thiocyanate,and nitrate in all samples was 15.2 ng/m L,404 ng/m L and 66.4 μg/m L,respectively.ICCs for these three chemicals ranged from 0.03 to 0.18 over the three trimesters.Spearman correlation coefficients for urinary concentrations of the three chemicals ranged from 0.26 to 0.56.Compared to women with normal body mass index(BMI)before pregnancy,overweight women had significantly higher perchlorate,and lean women had significantly lower nitrate.Besides,perchlorate and nitrate were higher in women with a university degree or above.Furthermore,the median concentration of perchlorate in urine samples collected in spring and winter was higher than in summer and autumn.Conclusion: Pregnant women in Wuhan,China were generally exposed to perchlorate,thiocyanate,and nitrate.Urinary perchlorate concentrations of pregnant women in this study were higher than pregnant women in other countries.Urinary concentrations of the three chemicals varied across trimesters.Pre-pregnancy BMI,maternal education,pregnant weight gain,and urine sample collection season may affect urinary concentrations of perchlorate,thiocyanate,and nitrate.Part 2: Associations of prenatal exposure to perchlorate,thiocyanate,and nitrate with child neurocognitive development at 2 years oldObjective: To explore associations of trimester-specific perchlorate,thiocyanate,and nitrate exposure with offspring neurocognitive development.Method: Participants were the same as the first part.Neurocognitive development of children was estimated using Bayley Scales of Infant Development at 2 years old.Multivariate linear regression models and generalized estimating equations(GEE)were used to evaluate relationships of urinary perchlorate,thiocyanate,and nitrate concentrations with offspring neurocognitive development.Then,weighted quantile sum (WQS)regression models were used to estimate associations of co-occurring exposure to the three chemicals during pregnancy and childhood with offspring neurocognitive development and the contribution of each chemical.Finally,the Bayesian kernel machine regression(BKMR)models were used to analyze the exposure-response relationships of perchlorate,thiocyanate,and nitrate exposure during pregnancy and childhood with offspring neurocognitive development and interaction effects of the three chemical.Result: After adjusting for potential confounders,thiocyanate exposure during the first and second trimester was negatively associated with offspring MDI.Nitrate exposure during the first trimester was negatively associated with offspring MDI.When both pregnancy and childhood exposures were included in the GEE model,only the first and second trimester thiocyanate exposure was significantly negatively correlated with offspring MDI scores.Significantly negative associations of WQS index at the first trimester and the second trimester with offspring MDI were found,and thiocyanate was the dominant contributor.BKMR results found no significant interaction effect of the three chemicals exposure on offspring neurocognitive development.Conclusion: Exposure to perchlorate,thiocyanate,and nitrate during the first and second trimester may impair offspring neurocognitive development and early pregnancy seems to be the sensitive window,especially for thiocyanate.Part 3: Mediation roles of thyroid hormones and oxidative stress in prenatal exposure to perchlorate,thiocyanate,and nitrate and child neurocognitive developmentObjective: To estimate associations of perchlorate,thiocyanate,and nitrate exposure with thyroid hormones and oxidative stress biomarkers levels,and to estimate whether thyroid hormones and oxidative stress biomarkers mediated the associations of perchlorate,thiocyanate,and nitrate exposure with offspring neurocognitive development.Method:(1)Based on the second part,430 mothers measured thyroid hormones during the second trimester,and 1005 children measured heel blood thyroid stimulating hormone(TSH).Multivariate linear regression models and GEE models were used to estimate associations of perchlorate,thiocyanate,and nitrate exposure with thyroid hormones of pregnant women and infants.Then,multivariate linear regression models were used to evaluate associations of maternal and infant thyroid hormones with offspring neurocognitive development.Finally,mediation analysis was conducted to estimate the mediation roles of maternal and infant thyroid hormones in prenatal perchlorate,thiocyanate,or nitrate exposure with offspring neurocognitive development.(2)The research subjects were the same as those in the second part.UPLC-MS/MS was used to detect three oxidative stress biomarkers including 8-hydroxy-2 ′-deoxyguanosine(8-OHd G,for DNA),8-hydroxyguanosine(8-OHG,for RNA),and 4-hydroxy nonenal mercapturic acid(HNEMA,for lipid)concentrations in urine.Linear mixed-effect models were used to estimate associations of perchlorate,thiocyanate,and nitrate exposure with maternal oxidative stress biomarkers during pregnancy.The GEE models were used to estimate trimester-specific associations between maternal oxidative stress biomarkers and offspring neurocognitive development.Finally,mediation analysis was conducted to estimate the mediation role of oxidative stress biomarkers.Result:(1)After adjusting for potential confounders,urinary concentrations of thiocyanate and nitrate were positively associated with FT4 levels of pregnant women.Maternal FT4 level was negatively associated with offspring MDI score.Average urinary thiocyanate during pregnancy was significantly associated with higher heel blood TSH concentrations of infants.Higher TSH level of infant was negatively associated with offspring MDI score.No significant mediation role of maternal FT4 or infant TSH was found in the association of maternal thiocyanate exposure and offspring neurocognitive development.(2)After adjusting for potential confounders,Perchlorate,thiocyanate,and nitrate exposure during pregnancy was associated increased 8-OHd G,8-OHG,and HNEMA levels.HNEMA level was negatively associated with offspring MDI score.The mediation analysis showed that about 15.92% of the effect of second trimester thiocyanate exposure on offspring MDI was mediated by maternal HNEMA level.Conclusion: Perchlorate,thiocyanate,and nitrate exposure during pregnancy may disrupt maternal and infant thyroid hormones,and are also associated with NDA,RNA,and lipid oxidative damage of pregnant women.Maternal lipid oxidative damage plays a significantly mediation role in maternal thiocyanate exposure and child neurocognitive development.