The Studies About The Associations Of Prenatal Exposure To Bisphenol A And Its Alternatives With The Fetal Growth

Bisphenol A(BPA)as one of synthetic chemicals with high production volume is broadly used to manufacture epoxy resins,polycarbonate,and polyurethane.Up till now,BPA has been widely detected in various environmental media and human’s biological samples.Accumulating evidence has shown that BPA is one of identified endocrine disrupting compounds(EDCs),with the endocrine disrupting effects,carcinogenicity,teratogenicity,reproductive toxicity,and developmental toxicity,which may cause adverse effect tofetal growth.Given increasing concern on the detrimental health effect of BPA,some countries have established the standards to ban its use in some consumer products.As a result,bisphenol analogs such as bisphenol F(BPF)and bisphenol S(BPS)are widely produced to replace the application of BPA.Because BPF and BPS are structurally similar to BPA,their similarly adverse effects on physiological systems are expected.To date,the conclusion on the relationship between maternal exposure to BPA during pregnancy and fetal growth has been inconsistent.Moreover,human data regarding the effects of maternal exposure to BPF and BPS during pregnancy on fetal growth is also lacking.Furthermore,it has been unclear whether metabolic enzyme genetic variations and epigenetic changes modify the associaitons of maternal exposure to BPA and its alternatives during pregnancy with fetal growth.In an established birth cohort of assisotions between prenatal environmental pollutant exposures and fetal growth,the concentrations of BPA and its alternatives(BPF and BPS)in maternal prenatal morning urine sample were measured as exposure biomarkers.Fetal ultrasound measures,anthropometric measures at birth,and gestational age were assessed as indicators of fetal growth.The associaitons of maternal prenatal exposure to BPA and its alternatives(BPF and BPS)with indicators of fetal growth were investigated.Moreover,Cytochrome P4502E1(CYP2E1)and Glutathione S-transferase Z1(GSTZ1)gene polymorphisms in maternal peripheral blood to indicate individual’s metabolic enzyme genetic variations were detected,and the interactions between maternal prenatal exposure to BPA and its alternatives(BPF and BPS)and CYP2E1 and GSTZ1 gene polymorphisms on indicators of fetal growth were further investigated.Also,DNA methylation in Alu and long interspersed nucleotide element-1(LINE-1)repetitive elements from cord blood samples were measured by pyrosequencing method,and the associaitons between maternal prenatal exposure to BPA DNA methylation in cord blood,and indicators of fetal growth were further examined.The results provided human evidence regarding the associations between maternal exposure to BPA and its alternatives during pregnancy and fetal growth.Part one: The associations between prenatal exposure to BPA and its alternatives and indicators of fetal growthObjective: To investigate the associations between prenatal exposure to BPA,BPF and BPS and indicators of fetal growth.Methods: A total of 1197 pregnant women who presented in a hospital in Wuhan,Hubei Province between July 2011 and June 2012 and in Xiaogan,Hubei Province between October 2011 and December 2013 to wait for delivery were recruited in this study.The concentrations of BPA,BPF,and BPS in maternal prenatal morning urine sample were measured as exposure biomarkers.Fetal ultrasound measures including biparietal diameter(BPD),head circumference(HC),femur length(FL),and abdominal circumference(AC)were measured from pregnant women who wait for delivery in Wuhan by ultrasonography(N=322).Anthropometric measures at birth including birth weight and birth length,as well gestational age were retrieved from the hospital’s medical records in Wuhan and in Xiaogan(N=1197).The associations of prenatal urinary BPA,BPF,and BPS concentrations with indicators of fetal growth(fetal ultrasound measures,anthropometric measures at birth,and gestational age)were estimated by multivariable adjusted models,and stratification analysis by fetal sex was further evaluated.Results: The detectable percentages of BPA,BPF,and BPS in maternal morning urine samples were 99.3%,71.1%,and 47.9%,respectively,with the mean concentrations of 0.73 μg/L,0.07 μg/L,and 0.02 μg/L,respectively.For the fetal ultrasound measures,a gender difference in association of maternal urinary BPA concentrations and fetal HC(P for interaction = 0.003)were observed;each ln-unit increase in maternal urinary BPA concentration was associated with a mean decrease of 0.10 cm(95%CI:-0.18,-0.02)among boys and a mean increase of 0.14 cm(95%CI: 0.00,0.28)among girls for HC.The associations were robust for urinary BPA concentrations modeled as tertiles into models(P< 0.05).No robust associations between prenatal exposure to BPF and BPS and fetal ultrasound parameters were observed.For the fetal anthropometric measures at birth,the estimated mean decrease in birth length for the highest vs.lowest exposure groups of maternal urinary BPA and BPF were 0.30 cm(95% CI:-0.45,-0.16)and 0.21cm(95% CI:-0.36,-0.07)(Both P for trends < 0.01),respectively.After stratification analysis by fetal sex,these associations tended to be stronger in girls.RCS analysis further indicated inverted U-shaped dose-response relationships between maternal urinary BPA and BPF concentrations and birth length(Both P for overall association ≤ 0.05 and P for non-linear association < 0.05).Moreover,maternal urinary BPS was associated with decreased gestational age(β =-0.20 weeks,95% CI:-0.36,-0.03 for the highest vs.lowest exposure groups,P for trend = 0.02).After stratification analysis by fetal sex,the associations only occurred in girls.RCS analysis further indicated a linear dose-response relationship between maternal urinary BPS concentrations and gestational age(P for overall association < 0.05 and P for non-linear association >0.05).Conclusions: Prenatal exposure to BPA,BPF,and BPS may cause detrimental effects on fetal growth,and these effects appeare to be sex-specific.Part two: The interactions between prenatal exposure to BPA and its alternatives and metabolic enzyme gene polymorphisms on indicators of fetal growthObjective: To investigate the interactions between prenatal exposure to BPA,BPF and BPS and CYP2E1 and GSTZ1 gene polymorphisms on indicators of fetal growth.Methods: A total of 438 pregnant women who provided the sufficient peripheral blood samples for the analyses of gene polymorphisms were included from the birth cohort study.There were no significant differences in demographics except for study city,education,and parity between subjects included in the current analysis and the total study popualaton.Taq Man probe method was used to detect single nucleotide polymorphisms(SNP)in two metabolic enzyme genetic variations including CYP2E1(rs2031920,rs3813867,and rs915906)and GSTZ1(rs7975)from maternal peripheral blood.Statistical interactions between prenatal urinary BPA,BPF,and BPS concentrations and CYP2E1 and GSTZ1 polymorphisms on indicators of fetal growth(birth weight,birth length,and gestational age)were examined by multivariable linear regression models.Result: Suggestive interactions between exposure categories of maternal urinary BPA and CYP2E1 gene rs3813867 polymorphisms on birth height,as well between exposure categories of maternal urinary BPA and CYP2E1 gene rs2031320 polymorphisms on gestational age were observed(Both P for interactions = 0.09),though there were no significant associations within strata(P> 0.05).Also,a suggestive interaction between exposure categories of maternal urinary BPS and CYP2E1 gene rs2031320 polymorphisms on birth length was observed(P for interaction = 0.07).After being stratified by CYP2E1rs2031320 genotype,a not significantly positive association in mothers with TT but a not significantly negative association in mothers with CT/TT was observed between exposure categories of maternal urinary BPA and birth weight(Both P> 0.05).Moreover,a suggestive interaction between exposure categories of maternal urinary BPS and GSTZ1 gene rs7975 polymorphisms on gestational age(P for interaction = 0.08)was observed.After stratification by GSTZ1 rs7975 genotype,a not significantly positive association in mothers with GG(P> 0.05)whereas a significantly negative association in mothers with CT/TT(P for trend = 0.02)was observed between exposure categories of maternal urinary BPA and gestational age,and the estimated mean decrease in gestational age for the highest vs.lowest exposed group was 0.42weeks(95% CI:-0.74,-0.09).No significant associations between exposure categories of maternal urinary BPF and CYP2E1 and GSTZ1 gene polymorphisms on birth weight,birth length,and gestational age were observed(P for interaction > 0.05).Conclusions: Matenal genetic variations of CYP2E1 and GSTZ1 may modify the impacts of prenatal exposure to BPA and BPS on fetal growth.Part three: The associations between prenatal exposure to BPA and its alternatives,DNA methylation in cord blood,and indicators of fetal growthObjective: To examine the associations between between prenatal exposure to BPA,BPF and BPS,DNA methylation in cord blood,and indicators of fetal growth.Methods: A total of 114 pregnant women were chose from the birth cohort study.There were no significant differences in demographics except for gestational weight gain between subjects included in the current analysis and the excluded popualaton in Wuhan.DNA methylation in Alu and LINE-1 from cord blood samples was measured by pyrosequencing method.The associations between prenatal exposure to BPA and its alternatives,DNA methylation in cord blood,and indicators of fetal growth(birth weight,birth length,and gestational age)were estimated by using multivariable linear regression models.Result: The median of DNA methylation in Alu and LINE-1from cord blood samples were 23.72% and 59.43%,respectively.After adjusting for potential confounders,Alu methylation decreased 0.54%(95% CI:-0.10%,-0.07%)and 0.34%(95% CI:95%CI:-0.80%,0.12%)in the middle and high exposure groups of maternal urinary BPA compared with the low exposed group,respectively,though there was no significant dose-response association(P for trend = 0.35).No significant associaitons of expose categories of maternal urinary BPF and BPS with Alu and LINE-1 DNA methylation in cord blood were observed.Moreover,the middle and high Alu DNA methylation levels in cord blood had mean decreased birth weight of 177.29 g(95% CI: 325.10,-29.48)and 63.23 g(95% CI:-213.28,86.82),respectively and also had mean decreased birth length of 0.33 cm(95% CI:-0.62,-0.03)and 0.08 cm(95% CI:-0.38,0.22),respectively,though there were no significant dose-response associaitons(P for trend = 0.42 and 0.62,respectively).No significant associations of LINE-1 DNA methylation in cord blood with birth weight,birth length,and gestational age were observed(P> 0.05).Conclusions: Prenatal exposure to BPA may alter DNA methylation in cord blood and further adversely affect birth weight and birth length.