Effects Of Gestational Exposure To Disinfection By-products On Fetal Growth And Mediation Role Of Oxidative Stress

Chlorine disinfection controlled the water-born diseases and improved the quality of drinking water since its invention in the 20th century.However,the disinfectant can react with the natural organic matters and produce disinfection by-products(DBPs).Animal studies showed that DBPs can cause adverse birth outcomes,but epidemiological evidence exploring the association between DBPs exposure and fetal growth was inconsistent and the underlying mechanisms were unknown.Most prior studies used external exposure assessment and ignored the variability of DBPs exposure during pregnancy,which can lead to exposure misclassification and reduce the accuracy of exposure risk assessment.Therefore,in this perspective cohort study,we used blood trihalomethanes(THMs)and urinary haloacetic acids(HAAs)in early,mid-and late pregnancy as internal biomarkers to explore the profiles,variability and predictors of DBPs exposure.Oxidative stress biomarkers in early,mid-and late pregnancy were also determined to represent the oxidative stress status of our study population.We used ultrasound measures and birth outcomes as proxies of fetal growth and assessed the associations between DBPs exposure,oxidative stress and fetal growth.The results will elucidate the effects of environmental exposure to DBPs on fetal growth and related mechanisms,which ultimately provide scientific basis for the risk estimation of environmental exposure to DBPs during gestation.Part One Profiles,variability and predictors of concentrations of blood trihalomethanes and urinary haloacetic acids during pregnancy.Objectives:To investigate the profiles,variability and predictors of concentrations of blood THMs and urinary HAAs across pregnancy.Methods:We totally recruited 1760 pregnant women during March 2015 and September 2017 from a maternal and child health hospital in Xiaogan City and collected their questionnaires and biospecimens during early(<14 weeks),mid(14–28 weeks)and late pregnancy(>28 weeks).Blood chloroform(TCM),bromodichloromethane(BDCM),dibromochloromethane(DBCM)and bromoform(TBM)in 4304 blood samples were determined using a headspace solid phase microextraction gas chromatography.Urinary dichloroacetic acid(DCAA)and trichloroacetic acid(TCAA)in 4165 urine samples were quantified by gas chromatography using liquid-liquid extraction.We calculated the concentrations of Br-THMs(sum of BDCM,DBCM and TBM)and TTHMs(sum of Br-THMs and TCM).We used intraclass correlation coefficients(ICCs)to assess the variability of these biomarkers and estimated their predictors using mixed models.Results:The detection rates of blood TCM,BDCM,DBCM,TBM and urinary TCAA and DCAA were 92.4%,79.4%,42.6%,48.5%,91.3%and 96.1%,respectively,and the median concentrations of blood TCM,BDCM and urinary TCAA were 10.1ng/L,0.81 ng/L and 1.6?g/L,respectively.Repeated measurements of blood TCM,BDCM,Br-THMs and TTHMs and urinary DCAA and TCAA uniformly exhibited high variability(ICCs?0.13);the use of a single measurement to classify gestational average exposure resulted in a high degree of exposure misclassification.Using mixed models,the sampling season was a strong predictor of all analyzed DBPs.Additionally,we detected a positive association of blood TCM and BDCM with household income,urinary DCAA with age,and urinary TCAA with tap water usage,education level and amount of tap water consumed.Inverse associations were found between blood BDCM and vegetable consumption,and between blood Br-THMs and TTHMs and time interval since the last bathing/showering.Conclusions:Our results indicated that blood THM and urinary HAA concentrations varied greatly over the course of pregnancy and were affected by sampling season,sociodemographic factors,recent water-use activities and dietary intake.Part Two Effects of gestational exposure to disinfection by-products on fetal growth.Objectives:To investigate the associations of blood THMs and urinary HAAs with fetal growth parameters during pregnancy.Methods:Based on the study population of Part One,we additionally collected ultrasound screen information during mid-and late pregnancy as well as birth outcomes from 1660 pregnant women.Based on the results of Part One,we used average blood THM and urinary HAA concentrations to represent the DBPs internal exposure during pregnancy.Multivariable linear models were used to evaluate the associations between DBPs exposure and gestational age and birth weight,whereas logistic models were used to assess the associations of DBPs exposure with small for gestational age(SGA)and large for gestational age(LGA).We used linear mixed models to assess the relationships between DBPs exposure and ultrasound measured abdominal circumference(AC),head circumference(HC),biparietal diameter(BPD),femur length(FL)and estimated fetal weight(EFW).We also explored the potential windows of susceptibility and sex difference of DBPs exposure on fetal growth.Results:After adjusting for relevant confounders,we found significant or suggestive positive assocaitons of blood BDCM with birth weight and risk of LGA(both P for trends<0.10).We also observed significant or suggestive dose-response relationships between blood TCM and risk of SGA,and between urinary TCAA and risk of LGA(both P for trends<0.10).Meanwhile,we found significant or suggestive negative associations of blood TCM,Br-THMs and TTHMs with AC and EFW(all P for trends<0.10).We also observed negative associations of blood TCM and TTHMs in mid-pregnancy with FL(both P<0.05).Additionally,we found that the significant associations between blood TCM and TTHMs and fetal growth were more obvious in mid-pregnancy,whereas the positive associations between blood BDCM and fetal weight were more significant in early pregnancy.The sex-stratified analyses indicated a sex difference in effects of exposure to DBPs on fetal growth.Conclusions:DBPs exposure during gestation was associated with decreased AC,FL and EFW,and associated with increased risks of SGA and LGA,which indicated DBPs exposure may adversely affect fetal growth.Part Three Associaitons between gestational DBPs exposure,oxidative stress and fetal growth.Objectives:To examine the associations of blood THMs and urinary HAAs with urinary biomarkers of oxidative stress and fetal growth among pregnant women.Methods:Based on the study population in Part One,we further determined three urinary oxidative stress biomarkers including 8-hydroxy-2-deoxyguanosine(8-OHd G),4-hydroxy-2-nonenal-mercapturic acid(HNE-MA),and 8-iso-prostaglandin F_2?(8-iso PGF_2?)using high-performance liquid chromatography and tandem mass spectrometry.We used ICCs to assess the variability of oxidative stress biomarkers during pregnancy.Associations of blood THMs and urinary HAAs with urinary8-OHd G,HNE-MA and 8-iso PGF2?were evaluated using linear mixed regression models and generalized additive mixed models.We also explored the mediation roles of oxidative stress biomarkers in the associations between DBPs exposure and fetal growth based on the results of Part Two.Results:Oxidative stress biomarkers varied substantially across pregnancy,with ICCs?0.12.After adjusting for relevant confounding factors,we observed positive dose-response relationships between blood Br-THMs and urinary HNE-MA,between blood TCM and TTHMs and urinary 8-OHd G and HNE-MA,and between urinary DCAA and TCAA and urinary 8-OHd G,HNE-MA and 8-iso PGF_2?(all P for trends<0.05).When we modeled DBP exposures as continuous variables,most aforementioned associations were linear.The mediation analyses showed that 8-OHd G mediated 8.8%and 9.9%of the negative associations between TCM and TTHMs exposure in mid-pregnancy and FL,respectively.Conclusions:Exposure to DBPs during pregnancy can increase maternal oxidative stress status,which may mediate the associations between DBPs exposure and impaired fetal growth.